Nitrogeneous cyclic ketone derivative, process for producing the same, and use

ABSTRACT

A novel compound represented by the formula (I):  
                 
 
wherein rings A and B each represents an optionally substituted aromatic ring, or rings A and B may be bonded to each other through linking between bonds or substituents thereof to form a ring; ring C represents a nitrogenous saturated heterocycle optionally having one or more substituents besides the oxo (provided that 2,3-dioxopyrrolidine ring is excluded); R 1  represents hydrogen, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; and  
                 
indicates a single bond or a double bond. It has high antagonistic activity against a tachykinin receptor, especially an SP receptor.

TECHNICAL FIELD

The present invention relates to a novel nitrogenous cyclic ketonederivative having excellent tachykinin receptor antagonistic activity, aprocess for producing the same, and use.

BACKGROUND ART

Tachykinin is a general name of a series of neuropeptides, and includes,in mammals, substance P (SP), neurokinin-A and neurokinin-B. Thesepeptides are known to exert various physiological activities by bindingto respective receptors present in a living body (neurokinin-1,neurokinin-2, neurokinin-3).

Among them, SP is one of the oldest and most extensively investigatedneuropeptide, and is a peptide composed of 11 amino acids which wasidentified in an equine intestinal tract extract for the first time in1931, and whose structure was determined in 1971.

SP is distributed widely over the central and peripheral nervous systemsand, in addition to the function as a primary sensory neurontransmitter, it has various physiological activities such asvasodilating activity, vascular permeability-enhancing activity, smoothmuscle contracting activity, neurocyte exciting activity, salivatingactivity, diuretic activity, immunological activity, and the like. Inparticular, it is known that SP released from a terminal of a spinaloccipital horn by a pain impulse transmits the pain signal to asecondary neuron, and that SP released from a peripheral terminalinduces an inflammatory reaction in its receptor. Accordingly, SP isconsidered to be involved in various disease conditions (for example,pain, headache, especially migraine, Alzheimer's disease, multiplesclerosis, cardiovascular modulation, a chronic inflammatory diseasesuch as rheumatoid arthritis, a respiratory disease such as asthma andallergic rhinitis, bowel inflammatory disease such as ulcerative colitisand Crohn's disease, ocular damage and ocular inflammation,proliferative vitreoretinopathy, irritable bowel syndrome, pollakiuria,psychosis, vomiting and the like) [see Review: Physiological Reviews,Vol. 73, p. 229-308 (published 1993); Journal of Autonomic Pharmacology,Vol. 13, p. 23-93 (published 1993)].

Currently, as compounds having SP receptor antagonistic activity,EP-A-436,334 describes a compound represented by the formula:

and the like; WO92/17449 describes a compound represented by theformula:

and the like; WO95/16679 describes a compound represented by theformula:

and the like; and JP-A 9-263585 describes a heterocyclic compoundrepresented by the formula:

wherein ring M is a heterocyclic ring having —N═C<, —CO—N< or —CS—N< asits partial structure:

; Ra and Rb are taken together to form ring A, or may be same ordifferent and each is a hydrogen atom or a substituent on ring M; eachof rings A and B is an optionally substituted homocyclic or heterocyclicring, and at least one is an optionally substituted heterocyclic ring;ring C is an optionally substituted homocyclic or heterocyclic ring;ring Z is an optionally substituted nitrogenous heterocyclic ring; and nis an integer of 1 to 6, or a salt thereof, and the like.

OBJECTS OF THE INVENTION

Currently, there is no compound found as an agent for treating variousdisease conditions described above which has excellent tachykininreceptor antagonistic activity (especially SP receptor antagonisticactivity) and which is sufficiently satisfactory in terms of the safetyand sustained activity. Accordingly, it is desired to develop a compoundwhose chemical structure is different from those of the above knowncompounds and which has excellent tachykinin receptor antagonisticactivity and can serve as a therapeutic agent capable of exhibiting asufficiently satisfactory clinical effect.

Accordingly, the objects of the present invention are to provide a novelcompound having high tachykinin receptor antagonistic activity,especially SP receptor antagonistic activity, a process for producingthe same, etc.

The other objects of the present invention are to provide apharmaceutical composition having high tachykinin receptor antagonisticactivity, especially SP receptor antagonistic activity, a tachykininreceptor antagonist, an abnormal urination improving agent, etc.

SUMMARY OF THE INVENTION

In view of the above circumstances, the present inventors have studiedintensively. As a result, the present inventors have found that anitrogenous cyclic ketone derivative represented by the followingformula (I) or its salt has unexpectedly potent tachykinin receptorantagonistic activity (especially SP receptor antagonistic activity)based on its characteristic chemical structure, and can serve as asufficiently satisfactory medicine. The present invention has beencompleted based on these findings.

That is, the present invention provides:

(1) A compound represented by the formula (I):

wherein each of rings A and B represents an optionally substitutedaromatic ring, or rings A and B may be bonded to each other throughlinking between bonds or substituents thereof to form a ring; ring Crepresents a nitrogenous saturated heterocyclic ring optionally havingone or more substituents besides the oxo (provided that2,3-dioxopyrrolidine ring is excluded); R¹ represents a hydrogen atom,an optionally substituted hydrocarbon group or an optionally substitutedheterocyclic group; and

represents a single bond or a double bond, or a salt thereof;

(2) The compound according to the above (1), wherein each of rings A andB represents an optionally substituted benzene ring, or the substituentson rings A and B may be taken together to form a dibenzotricyclic ring;

(3) The compound according to the above (1), which is represented by theformula (Ia):

wherein each symbol is as defined in the above (1), or a salt thereof;

(4) The compound according to the above (1), which is represented by theformula (Ib):

wherein each symbol is as defined in claim 1 or a salt thereof;

(5) The compound according to the above (1), which is represented by theformula (Ic):

wherein each symbol is as defined in the above (1), or a salt thereof;

(6) The compound according to the above (1), wherein each of rings A andB is a benzene ring which may have one to three substituents selectedfrom a halogen atom, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, or thering formed by binding between the bonds or substituents of rings A andB is a dibenzsuberane ring, dibenzosuberene ring, xanthene ring orthioxanthene ring;

(7) The compound according to the above (1), wherein R¹ is an optionallysubstituted benzyl;

(8) A prodrug of the compound according to the above (1), or a saltthereof;

(9) A process for producing the compound according to the above (1),which comprises reacting a compound represented by the formula (II):

wherein each symbol is as defined in the above (1), or a salt thereofwith a compound represented by the formula (III):

wherein each of X and Y represents a hydrogen atom, a hydroxyl group ora halogen atom, and other symbols are as defined in the above (1),provided that, when X is a hydrogen atom, then Y represents a hydroxylgroup or a halogen atom, while X is a halogen atom, then Y is a halogenatom, or a reactive derivative or a salt thereof;

(10) A pharmaceutical composition comprising the compound according tothe above (1), or a salt or a prodrug thereof;

(11) The pharmaceutical composition according to the above (10), whichis a tachykinin receptor antagonist;

(12) The pharmaceutical composition according to the above (11), whichis an agent for preventing or treating pollakiuria, incontinence ofurine, asthma, rheumatoid arthritis, osteoarthritis, pain, cough,itching, chronic obstructive pulmonary disease, irritable bowel disease,vomiting, depression, anxiety neurosis, obsessive-compulsive neurosis,panic disorder, manic-depressive psychosis, schizophrenia, mania,migraine, cancer, HIV infection, cardiovascular disorder, solardermatitis, hypogonadism, ataxia, cognitive disorder or circadian rhythmdisorder;

(13) A method for preventing or treating pollakiuria, incontinence ofurine, asthma, rheumatoid arthritis, osteoarthritis, pain, cough,itching, chronic obstructive pulmonary disease, irritable bowel disease,vomiting, depression, anxiety neurosis, obsessive-compulsive neurosis,panic disorder, manic-depressive psychosis, schizophrenia, mania,migraine, cancer, HIV infection, cardiovascular disorder, solardermatitis, hypogonadism, ataxia, cognitive disorder or circadian rhythmdisorder, which comprises administering an effective amount of thecompound according to the above (1), or a salt or a prodrug to thereofto a mammal; and

(14) Use of the compound according to the above (1), or a salt or aprodrug thereof for manufacturing an agent for preventing or treatingpollakiuria, incontinence of urine, asthma, rheumatoid arthritis,osteoarthritis, pain, cough, itching, chronic obstructive pulmonarydisease, irritable bowel disease, vomiting, depression, anxietyneurosis, obsessive-compulsive neurosis, panic disorder,manic-depressive psychosis, schizophrenia, mania, migraine, cancer, HIVinfection, cardiovascular disorder, solar dermatitis, hypogonadism,ataxia, cognitive disorder or circadian rhythm disorder.

Further, the present invention also provides:

(15) The pharmaceutical composition according to the above (10), whichis a substance P receptor antagonist;

(16) The pharmaceutical composition according to the above (10), whichis an agent for preventing or treating a disease associated withsubstance P;

(17) The pharmaceutical composition according to the above (10), whichis an abnormal urination improving agent;

(18) The pharmaceutical composition comprising a combination of aneffective amount of the compound according to the above (1) or a saltthereof or a prodrug thereof with an effective amount of one or moreagents selected from the group consisting of a diabetes treating agent,diabetic complication treating agent, anti-hyperlipidemic agent,hypotensive agent, anti-obesity agent, diuretic, chemotherapeutic agent,immunotherapeutic agent, cachexia improving agent, anti-inflammatoryagent, saccharification inhibitor, nerve regeneration promoting agent,anti-depressant, anti-epileptic agent, anti-arrhythmic agent,acetylcholine receptor ligand, endothelin receptor antagonistic agent,monoamine intake inhibitor, narcotic and anti-narcotic analgesic, GABAreceptor agonist, GABA intake inhibitor, α₂ receptor agonist, localanalgesic, protein kinase C inhibitor, anti-anxiety agent,phosphodiesterase inhibitor, dopamine receptor agonist or antagonist,serotonin receptor agonist or antagonist, serotonin intake inhibitor,sleepiness inducing agent, anti-cholinergic agent, α₁ receptor blocker,muscle relaxant, calcium channel opener, calcium channel blocker,Alzheimer's disease preventing or treating agent, Parkinson's diseasepreventing or treating agent, multiple sclerosis preventing or treatingagent, histamine H₁ receptor inhibitor, proton pump inhibitor,anti-thrombotic agent, NK-2 receptor antagonist, NK-3 receptorantagonist, antioxidant, sodium channel inhibitor and angiotensin IIreceptor antagonist;

(19) A method for preventing or treating pollakiuria or incontinence ofurine comprising administering to a mammal a combination of an effectiveamount of the compound according to the above (1) or a salt thereof or aprodrug thereof with an effective amount of one or more agents selectedfrom the group consisting of a diabetes treating agent, diabeticcomplication treating agent, anti-hyperlipidemic agent, hypotensiveagent, anti-obesity agent, diuretic, chemotherapeutic agent,immunotherapeutic agent, cachexia improving agent, anti-inflammatoryagent, saccharification inhibitor, nerve regeneration promoting agent,anti-depressant, anti-epileptic agent, anti-arrhythmic agent,acetylcholine receptor ligand, endothelin receptor antagonistic agent,monoamine intake inhibitor, narcotic and anti-narcotic analgesic, GABAreceptor agonist, GABA intake inhibitor, α₂ receptor agonist, localanalgesic, protein kinase C inhibitor, anti-anxietic agent,phosphodiesterase inhibitor, dopamine receptor agonist or antagonist,serotonin receptor agonist or antagonist, serotonin intake inhibitor,sleepiness inducing agent, anti-cholinergic agent, α₁ receptor blocker,muscle relaxant, calcium channel opener, calcium channel blocker,Alzheimer's disease preventing or treating agent, Parkinson's diseasepreventing or treating agent, multiple sclerosis preventing or treatingagent, histamine H₁ receptor inhibitor, proton pump inhibitor,anti-thrombotic agent, NK-2 receptor antagonist, NK-3 receptorantagonist, antioxidant, sodium channel inhibitor and angiotensin IIreceptor antagonist;

(20) A method for preventing or treating asthma, rheumatoid arthritis,osteoarthritis, pain, cough, itching, chronic obstructive pulmonarydisease, irritable bowel disease, vomiting, depression, anxietyneurosis, obsessive-compulsive neurosis, panic disorder,manic-depressive psychosis, schizophrenia, mania, migraine, cancer, HIVinfection, cardiovascular disorder, solar dermatitis, hypogonadism,ataxia, cognitive disorder or circadian rhythm disorder, comprisingadministering to a mammal a combination of an effective amount of thecompound according to the above (1) or a salt thereof or a prodrugthereof with an effective amount of one or more agents selected from thegroup consisting of a diabetes treating agent, diabetic complicationtreating agent, anti-hyperlipidemic agent, hypotensive agent,anti-obesity agent, diuretic, chemotherapeutic agent, immunotherapeuticagent, cachexia improving agent, anti-inflammatory agent,saccharification inhibitor, nerve regeneration promoting agent,anti-depressant, anti-epileptic agent, anti-arrhythmic agent,acetylcholine receptor ligand, endothelin receptor antagonistic agent,monoamine intake inhibitor, narcotic and anti-narcotic analgesic, GABAreceptor agonist, GABA intake inhibitor, α₂ receptor agonist, localanalgesic, protein kinase C inhibitor, anti-anxietic agent,phosphodiesterase inhibitor, dopamine receptor agonist or antagonist,serotonin receptor agonist or antagonist, serotonin intake inhibitor,sleepiness inducing agent, anti-cholinergic agent, α₁ receptor blocker,muscle relaxant, calcium channel opener, calcium channel blocker,Alzheimer's disease preventing or treating agent, Parkinson's diseasepreventing or treating agent, multiple sclerosis preventing or treatingagent, histamine H₁ receptor inhibitor, proton pump inhibitor,anti-thrombotic agent, NK-2 receptor antagonist, NK-3 receptorantagonist, antioxidant, sodium channel inhibitor and angiotensin IIreceptor antagonist.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, a C₁₋₆ alkyl may be a straight or branched alkyl andincludes, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

A C₂₋₆ alkenyl may be a straight or branched alkenyl, and includes, forexample, vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl andthe like.

Examples of a C₃₋₆ cycloalkyl include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like.

Examples of a C₆₋₁₄ aryl include phenyl, 1-naphthyl, 2-naphthyl,biphenyl, 2-anthryl and the like.

Examples of a halogen atom include fluorine, chlorine, bromine, iodineand the like.

In the compounds represented by the formulas (I), (Ia), (Ib) and (Ic)shown above (hereinafter sometimes referred to as the compounds (I),(Ia), (Ib) and (Ic), respectively), each of rings A and B represents anoptionally substituted aromatic ring, or rings A and B may be takentogether via the binding between their bonds or substituents to form aring.

Examples of the “aromatic ring” in the “optionally substituted aromaticring” represented by rings A and B include an aromatic hydrocarbon ring,aromatic heterocyclic ring and the like.

The “aromatic hydrocarbon ring” may for example be a monocyclic totricyclic aromatic hydrocarbon ring having 6 to 14 carbon atoms,typically benzene ring, naphthalene ring, indene ring, anthracene ringand the like.

The “aromatic heterocyclic ring” may for example be a 5- to 14-membered,preferably 5- to 10-membered aromatic heterocyclic ring containing oneor more (for example, 1 to 4) heteroatoms selected from nitrogen atoms,sulfur atoms and oxygen atoms in addition to carbon atoms. Specificexamples thereof include aromatic heterocyclic rings such as thiophene,benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole,benzisothiazole, naphtho[2,3-b]thiophene, furane, phenoxathine, pyrrole,imidazole, pyrazole, oxadiazole, pyridine, pyrazine, pyrimidine,pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine,isoquinoline, quinoline, phthaladine, naphthylidine, quinoxaline,quinazoline, cinnoline, carbazole, β-carboline, phenanthridine,acridine, phenadine, thiazole, isothiazole, phenothiazine, isoxazole,furazane, phenoxadine, phthalimide and the like, as well as rings formedby fusion of any of these rings (preferably a monocyclic ring) with oneor more (preferably 1 or 2) aromatic rings (for example, benzene ring,etc.).

The “aromatic ring” in the “optionally substituted aromatic ring”represented by rings A and B is preferably a monocyclic aromatichydrocarbon ring (i.e., benzene ring) or a monocyclic aromaticheterocyclic ring, more preferably a benzene ring.

Examples of the substituent on rings A and B include (1) a halogen atom(e.g., fluorine, chlorine, bromine, iodine and the like), (2) C₁₋₃alkylenedioxy (e.g., methylenedioxy, ethylenedioxy and the like), (3)nitro, (4) cyano, (5) optionally halogenated C₁₋₆ alkyl, (6) optionallyhalogenated C₂₋₆ alkenyl, (7) optionally halogenated C₂₋₆ alkynyl, (8)optionally halogenated C₃₋₆ cycloalkyl, (9) C₆₋₁₄ aryl (e.g., phenyl,1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl and the like), (10)optionally halogenated C₁₋₆ alkoxy, (11) optionally halogenated C₁₋₆alkylthio or mercapto, (12) hydroxy, (13) amino, (14) mono-C₁₋₆alkylamino (e.g., methylamino, ethylamino and the like), (15) mono-C₁₋₆arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino and thelike), (16) di-C₁₋₆ alkylamino (e.g., dimethylamino, diethylamino andthe like), (17) di-C₆₋₁₄ arylamino (e.g., diphenylamino and the like),(18) acyl, (19) acylamino, (20) acyloxy, (21) optionally substituted 5-to 7-membered saturated cyclic amino, (22) 5- to 10-membered aromaticheterocyclic group (e.g., 2- or 3-thienyl, 2-,3- or 4-pyridyl, 2-, 3-,4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or 3-indolyl,2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl and the like), (23)sulfo, (24) C₆₋₁₄ aryloxy (e.g., phenyloxy, naphthyloxy and the like)and the like.

Each of rings A and B may have 1 to 3, preferably 1 to 2 substituents inany substitutable positions, and when there are two or moresubstituents, each substituent may be the same or different.

The “optionally halogenated C₁₋₆ alkyl group” described above may forexample be a C₁₋₆ alkyl group (for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and thelike) which may have 1 to 5, preferably 1 to 3 halogen atoms (forexample, fluorine, chlorine, bromine, iodine and the like), and thelike. Specific examples thereof include methyl, chloromethyl,difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,6,6,6-trifluorohexyl and the like.

The “optionally halogenated C₂₋₆ alkenyl group” may for example be aC₂₋₆ alkenyl group (for example, vinyl, allyl, isopropenyl, butenyl,isobutenyl, sec-butenyl and the like) which may have 1 to 5, preferably1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodineand the like), and the like. Specific examples thereof include vinyl,allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl,3,3,3-trifluoro-1-propenyl, 4,4,4-trifluoro-1-butenyl and the like.

The “optionally halogenated C₂₋₆ alkynyl group” described above may forexample be a C₂₋₆ alkynyl group (for example, ethynyl, propargyl,butynyl, 1-hexynyl and the like) which may have 1 to 5, preferably 1 to3 halogen atoms (for example, fluorine, chlorine, bromine, iodine andthe like), and the like. Specific examples thereof include ethynyl,propargyl, butynyl, 1-hexynyl, 3,3,3-trifluoro-1-propynyl,4,4,4-trifluoro-1-butynyl and the like.

The “optionally halogenated C₃₋₆ cycloalkyl group” described above mayfor example be a C₃₋₆ cycloalkyl group (for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like) which may have 1 to 5,preferably 1 to 3 halogen atoms (for example, fluorine, chlorine,bromine, iodine and the like), and the like. Specific examples thereofinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl,4-chlorocyclohexyl and the like.

The “optionally halogenated C₁₋₆ alkoxy group” described above may forexample be a C₁₋₆ alkoxy group (for example, methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and thelike) which may have 1 to 5, preferably 1 to 3 halogen atoms (forexample, fluorine, chlorine, bromine, iodine and the like), and thelike. Specific examples thereof include methoxy, difluoromethoxy,trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy,butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy,hexyloxy and the like.

The “optionally halogenated C₁₋₆ alkylthio group” described above mayfor example be a C₁₋₆ alkylthio group (for example, methylthio,ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio,tert-butylthio and the like) which may have 1 to 5, preferably 1 to 3halogen atoms (for example, fluorine, chlorine, bromine, iodine and thelike), and the like. Specific examples thereof include methylthio,difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio,hexylthio and the like.

Examples of the “acyl” described above include formyl, carboxy,carbamoyl, C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl and the like),C₃₋₆ cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl and the like), C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl and the like), C₆₋₁₄ aryl-carbonyl (e.g., benzoyl,1-naphthoyl, 2-naphthoyl and the like), C₇₋₁₆ aralkyl-carbonyl (e.g.,phenylacetyl, phenylpropionyl and the like), C₆₋₁₄ aryloxy-carbonyl(e.g., phenoxycarbonyl and the like), C₇₋₁₆ aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl, phenethyloxycarbonyl and the like), 5-or 6-memberedheterocyclic carbonyl (e.g., nicotinoyl, isonicotinoyl, 2-thenoyl,3-thenoyl, 2-furoyl, 3-furoyl, morpholinocarbonyl,thiomorpholinocarbonyl, piperidinocarbonyl, 1-pyrrolidinylcarbonyl andthe like), mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl,ethylcarbamoyl and the like), di-C₁₋₆ alkyl-carbamoyl (e.g.,dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and the like),C₆₋₁₄ aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl,2-naphthylcarbamoyl and the like), thiocarbamoyl, 5-or 6-memberedheterocyclic carbamoyl (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl,4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and thelike), C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl and thelike), C₆₋₁₄ arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,2-naphthylsulfonyl and the like), C₁₋₆ alkylsulfinyl (e.g.,methylsulfinyl, ethylsulfinyl and the like), C₆₋₁₄ arylsulfinyl (e.g.,phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and the like) andthe like.

Examples of the “acylamino” described above include formylamino, C₁₋₆alkyl-carbonylamino (e.g., acetylamino and the like), C₆₋₁₄aryl-carbonylamino (e.g., phenylcarbonylamino, naphthylcarbonylamino andthe like), C₁₋₆ alkoxy-carbonylamino (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonyamino, butoxycarbonylamino and thelike), C₁₋₆ alkylsulfonylamino (e.g., methylsulfonylamino,ethylsulfonylamino and the like), C₆₋₁₄ arylsulfonylamino (e.g.,phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphtylsulfonylamino andthe like) and the like.

Examples of the “acyloxy group” described above include C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propionyloxy and the like), C₆₋₁₄aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy and the like),C₁₋₆ alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy,propoxycarbonyloxy, butoxycarbonyloxy and the like), mono-C₁₋₆alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy and thelike), di-C₁₋₆ alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,diethylcarbamoyloxy and the like), C₆₋₁₄ aryl-carbamoyloxy (e.g.,phenylcarbamoyloxy, naphtylcarbamoyloxy and the like), nicotinoyloxy andthe like.

Examples of the “5- to 7-membered saturated cyclic amino” in the“optionally substituted 5- to 7-membered saturated cyclic amino”described above include morpholino, thiomorpholino, piperazin-1-yl,piperidino, pyrrolidin-1-yl and the like. Examples of the “substituent”in the “optionally substituted 5- to 7-membered saturated cyclic amino”include C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), C₆₋₁₄ aryl (e.g.,phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl, etc.), 5- to10-membered aromatic heterocyclic group (e.g., 2- or 3-thienyl, 2-, 3-or4-pyridyl, 2-, 3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl,1-, 2- or 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,benzo[b]furanyl, etc.) and the like and, 1 to 3 of which may be used.

Examples of the ring which may be formed together with rings A and B asa result of the binding between their bonds or substituents includefluorene ring, indenopyridine ring, indenothiophene ring, indenofuranering, thienocyclopentapyridine ring, xanthene ring, thioxanthene ring,curomenopyridine ring, thienochromene ring, furochromene ring,thienopyranopyridine ring, dibenzosuberane ring, dibenzosuberene ring,benzocycloheptapyridine ring, benzocycloheptathiophene ring,benzocycloheptafurane ring, thienocycloheptapyridine ring and the like.

Preferably, each of rings A and B is a benzene ring which may besubstituted by 1 to 3 halogen atoms, preferably fluorine atoms.

R¹ represents a hydrogen atom, an optionally substituted hydrocarbongroup or an optionally substituted heterocyclic group.

The “hydrocarbon group” in the “optionally substituted hydrocarbongroup” represented by R¹ may for example be an aliphatic hydrocarbongroup, a monocyclic saturated hydrocarbon group and an aromatichydrocarbon group, with those having 1 to 16 carbon atoms beingpreferred. Specifically, an alkyl group, an alkenyl group, an alkynylgroup, a cycloalkyl group, an aryl group, an aralkyl group, etc. areused.

For example, the “alkyl group” is preferably a lower alkyl group. For,example, a C₁₋₆ alkyl group such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. is generallyused.

For example, the “alkenyl group” is preferably a lower alkenyl group.For example, a C₂₋₆ alkenyl group such as vinyl, 1-propenyl, allyl,isopropenyl, butenyl, isobutenyl, etc. is generally used.

For example, the “alkynyl group” is preferably a lower alkynyl group.For example, a C₂₋₆ alkynyl group such as ethynyl, propargyl,1-propynyl, etc. is generally used.

For example, the “cycloalkyl group” is preferably a lower cycloalkylgroup. For example, a C₃₋₆ cycloalkyl group such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, etc. is generally used.

For example, the “aryl group” is preferably a C₆₋₁₄ aryl such as phenyl,1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl and the like, and a phenylgroup, etc. are generally used.

For example, the “aralkyl group” is preferably a C₇₋₁₆ aralkyl groupsuch as benzyl, phenylethyl, phenylpropyl, phenylbutyl,α-naphthylmethyl, diphenylmethyl and the like, and benzyl, etc. aregenerally used.

Examples of the substituent which may be possessed by the “hydrocarbongroup” in the “optionally substituted hydrocarbon group” include ahalogen atom (for example, fluorine, chlorine, bromine, iodine and thelike), a nitro group, a cyano group, a hydroxyl group, an optionallyhalogenated lower alkyl group (for example, an optionally halogenatedC₁₋₆ alkyl group such as methyl, chloromethyl, difluoromethyl,trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 4,4,4-trifluorobutyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,6,6,6-trifluorohexyl and the like), an optionally halogenated loweralkoxy group (for example, a C₁₋₆ alkoxyl group such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy and thelike), an amino group, a mono-lower alkylamino group (for example, amono-C₁₋₆ alkylamino group such as methylamino, ethylamino and thelike), a di-lower alkylamino group (for example, a di-C₁₋₆ alkylaminogroup such as dimethylamino, diethylamino and the like), a mono-loweralkylamino-lower alkoxy group (for example, a mono-C₁₋₆ alkylamino-C₁₋₆alkoxy group such as methylaminoethoxy and the like), a di-loweralkylamino-lower alkoxy group (for example, a di-C₁₋₆ alkylamino-C₁₋₆alkoxy group such as diethylaminoethoxy and the like), a C₁₋₃alkylenedioxy (for example, methylenedioxy, ethylenedioxy,propylenedioxy), a carboxyl group, a lower alkylcarbonyl group (forexample, a C₁₋₆ alkyl-carbonyl group such as acetyl, propionyl and thelike), a lower alkoxycarbonyl group (for example, a C₁₋₆ alkoxy-carbonylgroup such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,butoxycarbonyl and the like), a carbamoyl group, a thiocarbamoyl group,a mono-lower alkyl carbamoyl group (for example, a mono-C₁₋₆alkyl-carbamoyl group such as methyl carbamoyl, ethylcarbamoyl and thelike), a di-lower alkylcarbamoyl group (for example, a di-C₁₋₆alkyl-carbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl andthe like), an arylcarbamoyl group (for example, a C₆₋₁₀ aryl-carbamoylgroup such as phenylcarbamoyl, naphthylcarbamoyl and the like), anoptionally substituted aryl group (for example, a C₆₋₁₀ aryl group suchas phenyl, naphthyl and the like), an aryloxy group (for example, aC₆₋₁₀ aryloxy group such as phenyloxy, naphthyloxy and the like), anoptionally halogenated lower alkylcarbonylamino group (for example, anoptionally halogenated C₁₋₆ alkyl-carbonylamino group such asacetylamino, trifluoroacetylamino and the like), an oxo group, a 5- to14-membered (preferably 5- to 10-membered) (monocyclic to tricyclic,preferably monocyclic or bicyclic) heterocyclic group containing 1 to 4(preferably 1 to 3) heteroatoms of 1 or 2 species selected fromnitrogen, oxygen and sulfur atoms in addition to carbon atoms (forexample, a 5-membered cyclic group containing 1 to 4 heteroatomsselected from oxygen, sulfur or nitrogen atoms in addition to carbonatoms such as 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrroryl, 1-,2- or 3-pyrrolidinyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-,4- or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 3-, 4- or 5-pyrazolyl, 2-,3- or 4-pyrazolidinyl, 2-, 4- or 5-imidazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1H- or 2H-tetrazolyl and the like, a 6-membered cyclicgroup containing 1 to 4 heteroatoms selected from oxygen, sulfur ornitrogen atoms in addition to carbon atoms such as 2-, 3- or 4-pyridyl,N-oxide-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxide-2-, 4- or5-pyrimidinyl, thiomorpholinyl, morpholinyl, piperidino, 2-, 3- or4-piperidyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl,piperazinyl, triazinyl, 3- or 4-pyridazinyl, pyrazinyl N-oxide-3 or4-pyridazinyl and the like, a bicyclic or tricyclic fused ring groupcontaining 1 to 4 heteroatoms selected from oxygen, sulfur or nitrogenatoms in addition to carbon atoms (preferably, a group formed by fusionof the 5- to 6-membered ring described above with one or two 5- to6-membered cyclic groups containing 1 to 4 heteroatoms selected fromoxygen, sulfur or nitrogen atoms in addition to carbon atoms) such asindolyl, benzofuryl, benzothiazolyl, benzoxazolyl, benzimidazolyl,quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl,indolidinyl, quinolidinyl, 1,8-naphthylidinyl, dibenzofuranyl,carbazolyl, acridinyl, phenanthridinyl, chromanyl, phenothiazinyl,phenoxazinyl and the like, preferably a 5- to 7-membered (preferably 5-or 6-membered) heterocyclic group containing 1 to 3 heteroatoms selectedfrom oxygen, sulfur or nitrogen atoms in addition to carbon atoms), atricyclic hydrocarbon group (for example,5H-dibenzo[a,d]cyclohepten-5-yl and the like), an imino group, a thioxogroup, C₁₋₆ alkylthio (e.g., methylthio), carboxy C₁₋₆ alkyl (e.g.,carboxymethyl), C₁₋₆ alkylsulfinyl (e.g., methylsulfinyl), mono-C₁₋₆alkylsulfonylamino (e.g., methylsulfonylamino), di-C₁₋₆alkylsulfonylamino (e.g., N,N-di(methylsulfonyl)amino) and the like. The“hydrocarbon group” in the “optionally substituted hydrocarbon group”may have 1 to 5, preferably 1 to 3 substituents described above at anysubstitutable positions in the hydrocarbon group, and when there are twoor more substituents, each substituent may be the same or different.

Examples of the “heterocyclic group” in the “optionally substitutedheterocyclic group” represented by R¹ include a 5- to 14-membered(preferably 5- to 10-membered) (monocyclic to tricyclic, preferablymonocyclic or bicyclic) heterocyclic group containing 1 to 4 (preferably1 to 3) heteroatoms of 1 or 2 species selected from nitrogen, oxygen andsulfur atoms in addition to carbon atoms. For example, a 5-memberedcyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfuror nitrogen atoms in addition to carbon atoms such as 2- or 3-thienyl,2- or 3-furyl, 1-, 2- or 3-pyrroryl, 1-, 2- or 3-pyrrolidinyl, 2-, 4- or5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4-or5-isothiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyrazolidinyl, 2-, 4-or 5-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyland the like, a 6-membered cyclic group containing 1 to 4 heteroatomsselected from oxygen, sulfur or nitrogen atoms in addition to carbonatoms such as 2-, 3- or 4-pyridyl, N-oxide-2-, 3- or 4-pyridyl, 2-, 4-or 5-pyrimidinyl, N-oxide-2-, 4- or 5-pyrimidinyl, thiomorpholinyl,morpholinyl, piperidino, 2-, 3- or 4-piperidyl, thiopyranyl,1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, 3-or 4-pyridazinyl, pyrazinyl N-oxide 3- or 4-pyridazinyl and the like, abicyclic or tricyclic fused ring group containing 1 to 4 heteroatomsselected from oxygen, sulfur or nitrogen atoms in addition to carbonatoms (preferably, a group formed by fusion of the 5- to 6-membered ringdescribed above with one or two 5- to 6-membered cyclic groupscontaining 1 to 4 heteroatoms selected from oxygen, sulfur or nitrogenatoms in addition to carbon atoms) such as indolyl, benzofuryl,benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl,phthalazinyl, quinazolinyl, quinoxalinyl, indolidinyl, quinolidinyl,1,8-naphthylidinyl, dibenzofuranyl, carbazolyl, acridinyl,phenanthridinyl, chromanyl, phenothiazinyl, phenoxazinyl and the likeare used. Among them, a 5- to 7-membered (preferably 5- or 6-membered)heterocyclic group containing 1 to 3 heteroatoms selected from oxygen,sulfur or nitrogen atoms in addition to carbon atoms are preferred.

Examples of the substituent which may be possessed by the “heterocyclicgroup” in the “optionally substituted heterocyclic group” include ahalogen atom (for example, fluorine, chlorine, bromine, iodine and thelike), a lower alkyl group (for example, a C₁₋₆ alkyl group such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl and the like), a cycloalkyl group (forexample, a C₃₋₆ cycloalkyl group such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like), a lower alkynyl group (forexample, a C₂₋₆ alkynyl group such as ethynyl, 1-propynyl, propargyl andthe like), a lower alkenyl group (for example, a C₂₋₆ alkenyl group suchas vinyl, allyl, isopropenyl, butenyl, isobutenyl and the like), anaralkyl group (for example, a C₇₋₁₁ aralkyl group such as benzyl,α-methylbenzyl, phenethyl and the like), an aryl group (for example, aC₆₋₁₀ aryl group such as phenyl, naphthyl and the like, preferablyphenyl group and the like), a lower alkoxy group (for example, a C₁₋₆alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, tert-butoxy and the like), an aryloxy group (forexample, a C₆₋₁₀ aryloxy group such as phenoxy and the like), a loweralkanoyl group (for example, a C₁₋₆ alkyl-carbonyl group such as formyl,acetyl, propionyl, butyryl, isobutyryl and the like), arylcarbonyl (forexample, a C₆₋₁₀ aryl-carbonyl group such as benzoyl, naphthoyl and thelike), a lower alkanoyloxy group (for example, a C₁₋₆ alkyl-carbonyloxygroup such as formyloxy, acetyloxy, propionyloxy, butyryloxy,isobutyryloxy and the like), an arylcarbonyloxy group (for example, aC₆₋₁₀ aryl-carbonyloxy group such as benzoyloxy, naphthoyloxy and thelike), a carboxyl group, a lower alkoxycarbonyl group (for example, aC₁₋₆ alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl isobutoxycarbonyl,tert-butoxycarbonyl and the like), aralkyloxycarbonyl (for example, aC₇₋₁₁ aralkyloxycarbonyl group such as benzyloxycarbonyl group and thelike), a carbamoyl group, a mono-, di- or tri-halogeno-lower alkyl group(for example, a mono-, di- or tri-halogeno-C₁₋₄ alkyl group such aschloromethyl, dichloromethyl, -trifluoromethyl, 2,2,2-trifluoroethyl andthe like), an oxo group, an amidino group, an imino group, an aminogroup, a mono-lower alkylamino group (for example, a mono-C₁₋₄alkylamino group such as methylamino, ethylamino, propylamino,isopropylamino, butylamino and the like), a di-lower alkylamino group(for example, a di-C₁₋₄ alkylamino group such as dimethylamino,diethylamino, dipropylamino, diisopropylamino, dibutylamino,methylethylamino and the like), a 3- to 6-membered cyclic amino groupwhich may contain 1 to 3 heteroatoms selected from oxygen, sulfur andnitrogen atoms in addition to carbon atoms and one nitrogen atom (forexample a 3- to 6-membered cyclic amino group such as aziridinyl,azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl,imidazolidinyl, piperidinyl, morpholinyl, dihydropyridyl, pyridyl,N-methylpiperazinyl, N-ethylpiperazinyl and the like), an alkylenedioxygroup (for example, a C₁₋₃ alkylenedioxy group such as methylenedioxy,ethylene dioxy and the like), a hydroxy group, a nitro group, a cyanogroup, a mercapto group, a sulfo group, a sulfino group, a phosphonogroup, a sulfamoyl group, a monoalkylsulfamoyl group (for example, amono-C₁₋₆ alkylsulfamoyl group such as N-methylsulfamoyl,N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl,N-butylsulfamoyl and the like), a dialkylsulfamoyl group (for example, adi-C₁₋₆ alkylsulfamoyl group such as N,N-dimethylsulfamoyl,N,N-diethylsulfamoyl, N,N-dipropylsulfamoyl, N,N-dibutylsulfamoyl andthe like), an alkylthio group (for example a C₁₋₆ alkylthio group suchas methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio and the like), an arylthio group (forexample a C₆₋₁₀ arylthio group such as phenylthio, naphthylthio and thelike), a lower alkylsulfinyl group (for example a C₁₋₆ alkylsulfinylgroup such as methylsulfinyl, ethylsulfinyl, propylsulfinyl,butylsulfinyl and the like), an arylsulfinyl group (for example, a C₆₋₁₀arylsulfinyl group such as phenylsulfinyl, naphthylsulfinyl and thelike), a lower alkylsulfonyl group (such as a C₁₋₆ alkylsulfoyl groupsuch as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl andthe like), an arylsulfonyl group (for example, a C₆₋₁₀ arylsulfonylgroup such as phenylsulfonyl, naphthylsulfonyl and the like).

The “heterocyclic group” in the “optionally substituted heterocyclicgroup” may have 1 to 5, preferably 1 to 3 substituents described aboveat any substitutable positions in the heterocyclic group, and when thereare two or more substituents, each substituent may be the same ordifferent.

R¹ is preferably an optionally substituted benzyl, i.e., a grouprepresented by the formula:

wherein R² is a hydrogen atom, C₁₋₆ alkyl or optionally substitutedC₆₋₁₄ aryl, R³, R⁴ , R⁵, R⁶ and R⁷ may be the same or different and eachrepresents a hydrogen atom, hydroxy, a halogen atom, an optionallyhalogenated C₁₋₆ alkyl group, C₆₋₁₄ aryl, C₆₋₁₄ aryloxy, optionallyhalogenated C₁₋₆ alkoxy, a substituted aminoethoxy group, C₁₋₃alkylenedioxy (for example, methylenedioxy), C₁₋₆ alkylthio, nitro,amino, cyano, carboxyl, carboxamide, mono- or di-C₁₋₆ alkylamino-C₁₋₆alkoxy (for example, diethylaminoethoxy), C₁₋₆ alkoxycarbonyl (forexample, methoxycarbonyl), carboxy alkyl (for example, carboxymethyl),carbamoyl, C₁₋₆ alkylsulfinyl (for example, methylsulfinyl), mono- ordi-C₁₋₆ alkylsulfomylamino (for example, di(methylsulfonyl)amino),heterocyclic group (for example, 1H-pyrrol-1-yl and the like),N-(optionally halogenated C₁₋₆ alkyl)-C₁₋₆ alkylsulfonylamino (forexample, N-2,2,2-trifluoroethyl-N-methylsulfonylamino), optionallyhalogenated C₁₋₆ alkyl-carbonylamino (for example, acetoamino,trifluoroacetoamino), alkoxycarbonylalkyl (for example,methoxycarbonylmethyl) or aroylalkoxycarbonylalkyl (for example,benzoylmethoxycarbonylmethyl).

Examples of each of the alkyl, aryl and halogen atom represented by R²,R³, R⁴, R⁵, R⁶ and R⁷ include a group similar to those in thesubstituents on rings A and B described above. The substituent on thearyl is, for example, a group similar to those in the substituents onrings A and B described above. Examples of the aliphatic acyl includeformyl, carboxy, carbamoyl, C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyland the like), C₃₋₆ cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl and the like), C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl and the like), mono-C₁₋₆ alkyl-carbamoyl (e.g.,methylcarbamoyl, ethylcarbamoyl and the like), di-C₁₋₆ alkyl-carbamoyl(e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and thelike), thiocarbamoyl, C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl,ethylsulfonyl and the like) and the like. Examples of the substitutedamino include mono-C₁₋₆ alkylamino (e.g., methylamino, ethylamino andthe like), mono-C₆₋₁₄ arylamino (e.g., phenylamino, 1-naphthylamino,2-naphthylamino and the like), di-C₁₋₆ alkylamino (e.g., dimethylamino,diethylamino and the like), di-C₆₋₁₄ arylamino (e.g., diphenylamino andthe like), optionally substituted 5- to 7-membered saturated cyclicamino described above and the like.

Ring C represents a nitrogenous saturated heterocyclic ring which may besubstituted in addition to the oxo.

Examples of the nitrogenous saturated heterocyclic ring include a 5- to7-membered saturated heterocyclic ring such as pyrrolidine, piperidine,perhydroazepine and the like, provided that a 2,3-dioxopyrrolidine ringis excluded.

Examples of the substituent on the nitrogenous saturated heterocyclicring include a group similar to the “optionally substituted hydrocarbongroup” in R¹ described above. Preferred examples thereof include (1)C₁₋₆ alkyl which may have one or more substituents selected from (a)hydroxyl, (b) oxo, (c) C₁₋₆ alkoxy, (d) phenyl-C₁₋₃ alkoxy, (e) phenyl,(f) cyano, (g) halogen atom, (h) —NR⁸R⁹ wherein each of R⁸ and R⁹independently represents a hydrogen atom, C₁₋₆ alkyl, hydroxy-C₁₋₆ alkylor phenyl, (i) —NR⁸COR⁹ wherein R⁸ and R⁹ are as defined above, (j)—NR⁸CO₂R⁹ wherein R⁸ and R⁹ are as defined above, (k) —CONR⁸R⁹ whereinR⁸ and R⁹ are as defined above, (1) —COR⁸ wherein R⁸ is as definedabove, (m) —CO₂R⁸ wherein R⁸ is as defined above, (2) C₂₋₆ alkenyl whichmay have one or more substituents selected from (a) to (m) in (1)described above, (3) C₂₋₆ alkynyl, (5) a phenyl group which may have oneor more substituents selected from (a) to (m) in (1) described above,and the like. Ring C may have 1 to 4, preferably 1 to 3 substituents atany substitutable positions, and when there are two or moresubstituents, each substituent may be the same or different.

In the formula (I),

represents a single bond or a double bond. A single bond is preferred.

Preferably, the compound (I) is the compound represented by the formulas(Ia), (Ib) and (Ic). More preferably, it is the compound represented bythe following formulas (Ia′), (Ib′) and (Ic′):

In the formula (Ia′), R^(a1), R^(a2) and R^(a3) are the same ordifferent, and each represents a hydrogen atom or an optionallysubstituted hydrocarbon group. As the hydrocarbon group, the groupexemplified with respect to the above ring C can be used. Preferably,R^(a1), R^(a2) and R^(a3) are hydrogen atoms.

In the formula (Ib′), R^(b1), R^(b2) and R^(b3) are the same ordifferent, and each represents a hydrogen atom or an optionallysubstituted hydrocarbon group. As the hydrocarbon group, the groupexemplified with respect to the above ring C can be used. Preferably,R^(b1), R^(b2) and R^(b3) are hydrogen atoms.

In the formula (Ic′), R^(c1) and R^(c2) are the same or different, andeach represents a hydrogen atom or an optionally substituted hydrocarbongroup. As the hydrocarbon group, the group exemplified with respect tothe above ring C can be used. Preferably, R^(c1) and R^(c2) are hydrogenatoms.

Examples of the salts of the compounds (I), (Ia), (Ib) and (Ic) includedmetal salts, ammonium salts, salts with organic bases, salts withinorganic acids, salts with organic acids, salts with basic or acidicamino acids and the like. Preferred examples of the metal salt includean alkaline metal salt such as a sodium salt, a potassium salt and thelike; an alkaline earth metal salt such as a calcium salt, a magnesiumsalt, a barium salt and the like; an aluminum salt; and the like.Preferred examples of the salt with an organic base include a salt withtrimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,dicyclohexylamine, N,N′-dibenzylethylenediamine and the like. Preferredexamples of the salt with an inorganic acid include a salt withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like. Preferred examples of the salt with anorganic acid include a salt with formic acid, acetic acid,trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like. Preferred examples of the salt with a basic amino acid includea salt with arginine, lysine, ornithine and the like. Preferred examplesof the salt with an acidic amino acid include a salt with aspartic acid,glutamic acid and the like.

Among them, pharmaceutically acceptable salts are preferred. Forexample, when the compound has an acidic functional group in itsmolecule, examples thereof include an inorganic salt such as an alkalinemetal salt (e.g., sodium salt, potassium salt and the like) and analkaline earth metal salt (e.g., calcium salt, magnesium salt, bariumsalt and the like), an ammonium salt and the like. When the compound hasa basic functional group in its molecule, examples thereof include asalt with an inorganic acid such as hydrochloric acid, hydrobromic acid,nitric acid, sulfuric acid, phosphoric acid and the like as well as asalt with an organic acid such as acetic acid, phthalic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinicacid, methanesulfonic acid, p-toluenesulfonic acid and the like.

The prodrug of the compound (I) of the present invention or a saltthereof means a compound which is converted into the compound (I) underphysiological conditions in a living body by a reaction with an enzymeor gastric acid, that is, a compound which is converted into thecompound (I) by an enzymatic oxidation, reduction, hydrolysis, etc., anda compound which is converted into the compound (I) by hydrolysis, etc.,with gastric acid, etc.

Examples of the prodrug of the compound (I) of the present inventioninclude a compound obtained by subjecting an amino group in the compound(I) to acylation, alkylation or phosphorylation (e.g., a compoundobtained by subjecting an amino group in the compound (I) of the presentinvention to eicosanoylation, alkanylation, pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation,tert-butylation, etc.); a compound obtained by subjecting a hydroxylgroup in the compound (I) of the present invention to acylation,alkylation, phosphorylation or boration (e.g., a compound obtained bysubjecting an hydroxyl group in the compound (I) of the presentinvention to acetylation, palmitoylation, propanoylation, pivaloylation,succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation, etc.); a compound obtained bysubjecting a carboxyl group in the compound (I) of the present inventionto esterification or amidation (e.g., a compound obtained by subjectinga carboxyl group in the compound (I) of the present invention to ethylesterification, phenyl esterification, carboxymethyl esterification,dimethylamino esterification, pivaloyloxymethyl esterification,ethoxycarbonyloxyethyl esterification, phthalidyl esterification,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification,cyclohexyloxycarbonylethyl esterification and methylamidation) and thelike. Any of these compounds can be produced from the compound (I) ofthe present invention by a method known per se.

The prodrug of the compound (I) of the present invention may also be acompound which is converted into the compound (I) under physiologicalconditions such as those described in “IYAKUHIN no KAIHATSU (Developmentof Medicines)”, Vol. 7, Design of Molecules, p. 163-198, Published byHIROKAWA SHOTEN (1990).

The present invention includes a solvate, for example, a hydrate of thecompound represented by the formula (I) or a salt thereof. Further, thecompound represented by the formula (I) may be labeled with an isotope(for example, ³H, ¹⁴C, ³⁵S, ¹²⁵I and the like) and the like.

The compound (I) of the present invention or its salt may be present asa stereoisomer based on its double bond or an amide structure such as acis- or trans-isomer as well as an optical isomer based on itsasymmetric carbon such as an R- or S-form, and the present inventionincludes both of a mixture of these isomers and a single compound.

The compound (I) of the present invention or its salt can be producedfor example by reacting a compound represented by the formula:

wherein each symbol is as defined above (hereinafter referred to as thecompound (II)) or a salt thereof with a compound represented by theformula:

wherein each of X and Y represents a hydrogen atom, a hydroxyl group ora halogen atom, and other symbols are as defined above, provided thatwhen X is a hydrogen atom, then Y is a hydroxyl group or a halogen atom,while when X is a halogen atom, then Y is a halogen atom (hereinafterreferred to as the compound (III)) or a reactive derivative thereof or asalt thereof in the presence of a trialkylsilyl triflate. If necessary,an acid catalyst such as a Lewis acid may be added.

The trialkylsilyl triflate is not specifically limited, buttrimethylsilyl trifluoromethanesulfonate is preferred. The amount of thetrialkylsilyl triflate is 1 to 10 molar equivalents, preferably 1 to 4molar equivalents per mole of the compound (II) or a salt thereof.

The acid catalyst is not limited particularly and a mineral acid or aLewis acid may be used. Preferred examples thereof include a zinc saltsuch as zinc chloride, zinc bromide, zinc iodide and the like, analuminum salt such as aluminum chloride, an iron salt such as ironchloride, a halogenated boron such as boron trifluoride, with a zincsalt such as zinc chloride being especially preferred. The amount of acatalyst to be used is 0.001 to 1 molar equivalent, preferably 0.1 to 1molar equivalent per mole of the compound (II) or a salt thereof. When abenzhydrol derivative is used as the compound (III) (in case that X is ahydrogen atom and Y is a hydroxyl group in the compound (III)), acatalyst is not required particularly, but may be added under certaincircumstances. The benzhydrol derivative used in this step is known orcan be readily produced from a corresponding benzophenone derivative bya known method [for example, Chem. Ber. 103, 2041-2051 (1970)]. Theamount of the compound (III) to be used is 1 to 5 molar equivalents,preferably 1 to 3 molar equivalents per mole of the compound (II) or asalt thereof. Usually, the reaction is carried out in a solvent which isinert to the reaction. Preferred examples of the solvent to be usedinclude aprotic solvents such as halogenated hydrocarbons such asdichloromethane, dichloroethane, chloroform and the like; nitrites suchas acetonitrile and the like; esters such as ethyl acetate and the like;ethers such as dimethoxyethane, tetrahydrofurane, dioxane and the like;hydrocarbons such as benzene, toluene and the like; amides such asdimethylformamide, hexamethylphosphoramide and the like; sulfoxides suchas dimethylsulfoxide and the like. In particular, halogenatedhydrocarbons such as dichloromethane, dichloroethane and the like arepreferred. The reaction temperature is usually −78° C. to the boilingpoint of the solvent, with a temperature from −50° C. to roomtemperature being especially preferred. The time required for thereaction may vary depending on the type of the compound (II) or a saltthereof, the type of the compound (III), the reaction temperature andother reaction conditions, and is usually 1 to 96 hours, preferably 1 to24 hours.

In this reaction, an enol ether of the compound (II) may be employed asthe starting compound instead of the compound (II). Examples of the enolether include alkyl enol ether, silyl enol ether and the like, withsilyl enol ether such as trimethylsilyl enol ether, triethylsilyl enolether and triisopropylsilyl enol ether being preferred.

Alternatively, the compound (I) of the present invention or its salt canbe produced by reacting a compound represented by the formula:

wherein each symbol is as defined above (hereinafter referred to as thecompound (IV)) or a salt thereof with a reactive derivative of acompound represented by the formula: R¹—OH wherein R¹ is as definedabove, or a salt thereof, which is an alkylating or acylating agent.

The compound (IV) to be used as the starting compound can be produced bysubjecting the compound (I) which is obtained by the method describedabove and has, as R¹, a group employed as a protective group such asacyl, alkyl, benzyl and the like to a known deprotection reaction or areaction analogous thereto depending on the type of R¹ [for example, themethod described in Protective Groups in Organic Synthesis, 3^(rd)edition, Theodara W. Greene, Peter G. M. Wuts, Wiley-Interscience,1999].

As the reactive derivative of the compound represented by the formula:R¹—OH or a salt thereof, for example, a compound represented by theformula: R¹-L wherein L is a leaving group and R¹ is as defined above(hereinafter simply referred to as the reactive derivative) or a saltthereof can be used.

Examples of the leaving group represented by L include a hydroxy group,a halogen atom (for example, chlorine atom, bromine atom, iodine atomand the like), a substituted sulfonyloxy group (for example, a C₁₋₆alkylsulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy andthe like; a C₆₋₁₄ arylsulfonyloxy group such as benzenesulfonyloxy,p-toluenesulfonyloxy and the like; a C₇₋₁₆ aralkylsulfonyloxy group suchas benzylsulfonyloxy group), an acyloxy group (acetoxy, benzoyloxy andthe like), an oxy group substituted with a heterocyclic ring or an arylgroup (succinyl imide, benzotriazole, quinoline, 4-nitrophenyl and thelike), a heterocyclic group (imidazole, alkylimidazole) and the like.

The reaction using the reactive derivative described above as thealkylating agent can be carried out by reacting the reactive derivativein the presence of a base in a solvent. Examples of the solvent includealcohols such as methanol, ethanol, propanol and the like, ethers suchas dimethoxyethane, dioxane tetrahydroethane and the like, ketones suchas acetone and the like, amides such as N,N-dimethylformamide and thelike, sulfoxides such as dimethylsulfoxide and the like. These solventsmay be appropriately mixed. Examples of the base include organic basessuch as trimethylamine, triethylamine, N-methylmorpholine, pyridine,picoline, N,N-dimethylaniline and the like, and inorganic bases such aspotassium carbonate, sodium carbonate, potassium hydroxide, sodiumhydroxide and the like. Further, examples of the reactive derivativeinclude optionally substituted alkane halides (for example, chloride,bromide, iodide and the like), sulfate esters, sulfonate esters (forexample, methanesulfonate, p-toluenesulfonate, benzenesulfonate and thelike) and the like, with a halide being preferred especially.

The amount of the reactive derivative to be used is, for example, 1 to 5equivalents, preferably 1 to 3 equivalents per mole of the substrate.The reaction temperature is usually −10° C. to 200° C., preferably about0° C. to 110° C., and the reaction time is usually 0.5 to 48 hours,preferably 0.5 to 16 hours.

When the leaving group L in the reactive derivative described above is ahydroxyl group, the reaction can also be carried out by reacting anorganophosphorous compound in the presence of a base according to, forexample, JP-A 58-43979. Examples of the organophosphorous compound to beused here include alkyl o-phenylenephosphates such as methylo-phenylenephosphate, ethyl o-phenylenephosphate (EPPA) and the like,and aryl o-phenylenephosphates such as phenyl o-phenylenephosphate,p-chlorophenyl o-phenylenephosphate and the like, with EPPA beingespecially preferred. Examples of the base include alkylamines such astrimethylamine, triethylamine, diisopropylethylamine, tri(n-butyl)amine,di(n-butyl)amine, diisobutylamine, dicyclohexylamine and the like, andcyclic amines such as pyridine, 2,6-lutidine and the like, with anorganic tertiary amine such as diisopropylethylamine being preferred.The amounts of the reactive derivative, base and organophosphorouscompound described above vary depending on the types of the compound(IV), reactive derivative, base and solvent described above as well asother reaction conditions. Usually, each of them is used in an amount ofabout 1 to about 10 moles, preferably about 1 to about 5 moles per moleof the compound (IV). The reaction is usually carried out in a solventinert to the reaction. Examples of the solvent to be used includeaprotic solvents, for example, halogenated hydrocarbons such asdichloromethane, dichloroethane, chloroform and the like; nitrites suchas acetonitrile and the like; esters such as ethyl acetate and the like;ethers such as dimethoxyethane, tetrahydrofurane, dioxane and the like;hydrocarbons such as benzene, toluene and the like; amides such asdimethylformamide, hexamethylphosphoramide and the like; sulfoxides suchas dimethylsulfoxide and the like, with halogenated hydrocarbons such asdichloromethane, dichloroethane and the like being preferred.

The reaction temperature is usually −78° C. to 200° C., preferably about−20° C. to about 150° C., and the reaction time varies depending on thetype of the compound (IV), reactive derivative, base and solvent to beused as well as other reaction conditions, and, for example, about 1 toabout 72 hours, preferably about 1 to about 24 hours.

For example, the reaction using the reactive derivative described aboveas the acylating agent is usually carried out in a solvent optionallywith a base for promoting the reaction advantageously, while thereaction varies depending on the types of the reactive derivative, baseand solvent. Examples of the solvent include hydrocarbons such asbenzene, toluene and the like, ethers such as ethyl ether, dioxane,tetrahydrofuran and the like, esters such as ethyl acetate and the like,halogenated hydrocarbons such as chloroform, dichloromethane and thelike, amides such as N,N-dimethylformamide and the like, and aromatichydrocarbons such as pyridine and the like. Examples of the base includebicarbonates such as sodium bicarbonate, potassium bicarbonate and thelike, carbonates such as sodium carbonate, potassium carbonate and thelike, acetates such as sodium acetate and the like, tertiary amines suchas triethylamine, and aromatic amines such as pyridine and the like.

Examples of the reactive derivative as the acylating agent describedabove to be used include acid anhydrides, mixed anhydrides, acid halides(for example, chloride, bromide), heterocyclic ring or aryl(succinimide, benzotriazole, quinoline, 4-nitrophenyl and the like)esters, heterocyclic ring (imidazole, alkylimidazole) amides and thelike.

The amount of the reactive derivative to be used is usually 1 to 10molar equivalents, preferably 1 to 3 molar equivalents per mole of asubstrate. The reaction temperature is usually −10° C. to 150° C.,preferably about 0° C. to 100° C., and the reaction time is usually 15minutes to 24 hours, preferably 30 minutes to about 16 hours.

The compound (I) or its salt can also be produced by reacting thecompound (IV) with an aldehyde in the presence of a reducing agent suchas a metal hydride. Examples of the metal hydride as the reducing agentinclude sodium borohydride, lithium borohydride, zinc borohydride,sodium cyanoborohydride, sodium triacetoxyborohydride, lithiumcyanoborohydride, lithium aluminum hydride and the like. The preferredmetal halide includes sodium borohydride, sodium cyanoborohydride,sodium triacetoxyborohydride and the like. The amount of the reducingagent to be used is, for example, 1 to 50 equivalents, preferably 1 to10 equivalents per mole of the substrate. As the aldehyde, formalin or aC₁₋₅ alkyl-aldehyde (e.g., acetoaldehyde) is used and the amount thereofis 1 to 100 equivalents, preferably 1 to 20 equivalents per mole of thesubstrate. As a reaction solvent, for example, lower alcohols such asmethanol, ethanol and the like, ethers such as dioxane, tetrahydrofuran,and the like, and hydrocarbons such as benzene, toluene and the like areexemplified. They can be used alone or in combination with each other.The reaction temperature is usually −80° C. to 40° C., preferably 50° C.to about 25° C., and the reaction time is usually 5 minutes to 48 hours,preferably 1 hour to 24 hours.

If necessary, the compound thus obtained can be subjected to oxidation,reduction, alkylation, acylation, substitution, condensation and thelike or a combination thereof by a known method or a method analogousthereto, whereby effecting further modification of the structure.

The starting compound is a known compound or can be produced by a methodknown per se. For example, the compound (II) can be produced by-reactinga compound represented by the formula:

wherein ring C is as defined above (hereinafter referred to as thecompound (V)) and the reactive derivative described above with anorganophosphorous compound in the presence of a base according to themethod described, for example, in JP-A 58-43979. Examples of theorganophosphorous compound to be used here include alkylo-phenylenephosphates such as methyl o-phenylenephosphate, ethylo-phenylenephosphate (EPPA) and the like, aryl o-phenylenephosphatessuch as phenyl o-phenylenephosphate, p-chlorophenyl o-phenylenephosphateand the like, with EPPA being especially preferred. Examples of the baseto be used include alkylamines such as trimethylamine, triethylamine,diisopropylethylamine, tri(n-butyl)amine, di(n-butyl)amine,diisopropylbutylamine, dicyclohexylamine and the like, cyclic aminessuch as pyridine, 2,6-lutidine and the like, with an organic tertiaryamine such as diisopropylethylamine being preferred. The amounts of thereactive derivative, base and organophosphorous compound described abovevary depending on the types of the compound (V), reactive derivative,base and solvent used as well as other reaction conditions, and usuallyeach amount is about 1 to about 10 moles, preferably about 1 to about 5moles per mole of the compound (V). The reaction is carried out usuallyin a solvent inert to the reaction. Examples of the solvent includeaprotic solvents such as halogenated hydrocarbons, for example,dichloromethane, dichloroethane, chloroform and the like; nitrites suchas acetonitrile and the like; esters such as ethyl acetate and the like;ethers such as dimethoxyethane, tetrahydrofuran, dioxane and the like;hydrocarbons such as benzene, toluene and the like; amides such asdimethylformamide, hexamethylphosphoramide and the like; sulfoxides suchas dimethylsulfoxide and the like, with halogenated hydrocarbons such asdichloromethane, dichloroethane and the like being preferred.

The reaction temperature is usually about −78° C. to about 200° C.,preferably about −20° C. to about 150° C., and the reaction time variesdepending on the type of the compound (V), reactive derivative, base andsolvent used as well as other reaction conditions, and for example isabout 1 to about 72 hours, preferably about 1 to about 24 hours.

In each of the reactions for synthesizing the desired compound andstarting compounds, when the starting compound has an amino group, acarboxy group or a hydroxy group as its substituent, such a group may beprotected by a protective group such as that generally used in a peptidechemistry. In this case, the desired compound can be obtained bydeprotection if necessary after the reaction.

As such a protective group, there is, for example, that described inProtective Groups in Organic Synthesis, 3^(rd) edition, Theodara W.Greene, Peter G. M. Wuts, Wiley-Interscience, 1999. Examples of theprotective group for an amino group include a C₁₋₆ alkyl-carbonyl group(for example, formyl, acetyl, propionyl groups, etc.), a phenylcarbonylgroup, a C₁₋₆ alkyl-oxycarbonyl group (for example, methoxycarbonyl,ethoxycarbonyl groups, etc.), an aryloxycarbonyl group (for example,phenyloxycarbonyl group, etc.), a C₇₋₁₀ aralkyl-carbonyl group (forexample, benzyloxycarbonyl group, etc.), a benzyl group, a benzhydrylgroup, a trityl group, a phthaloyl group and the like, any of which maybe substituted. Examples of the substituent include a halogen atom (forexample, fluorine, chlorine, bromine, iodine atoms), a C₁₋₆alkyl-carbonyl group (for example, acetyl, propionyl, butylcarbonylgroups, etc.), a nitro group and the like, and the number of thesubstituents is about 1 to 3.

Examples of the protective group for a carboxy group include a C₁₋₆alkyl group (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl,tert-butyl groups, etc.), a phenyl group, a trityl group, a silyl groupand the like, any of which may be substituted. Examples of thesubstituent include a halogen atom (for example, fluorine, chlorine,bromine, iodine atoms), a C₁₋₆ alkylcarbonyl group (for example, formyl,acetyl, propionyl, butylcarbonyl groups, etc.), a nitro group and thelike, and the number of the substituents is about 1 to 3.

Examples of the protective group for a hydroxy group include a C₁₋₆alkyl group (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl,tert-butyl groups, etc.), a phenyl group, a C₇₋₁₀ aralkyl group (forexample, benzyl group, etc.), a C₁₋₆ alkylcarbonyl group (for example,formyl, acetyl, propionyl groups, etc.), an aryloxycarbonyl group (forexample, phenyloxycarbonyl group, etc.), a C₇₋₁₀ aralkyl-carbonyl group(for example, benzyloxycarbonyl group, etc.), a pyranyl group, a furanylgroup, a silyl group and the like, any of which may be substituted.Examples of the substituent include a halogen atom (for example,fluorine, chlorine, bromine, iodine atoms), a C₁₋₆ alkyl group, a phenylgroup, a C₇₋₁₀ aralkyl group, a nitro group and the like, and the numberof the substituents is about 1 to 4.

The deprotection can be carried out by a method known per se or a methoddescribed in Protective Groups in Organic Synthesis, 3^(rd) edition,Theodara W. Greene, Peter G. M. Wuts, Wiley-Interscience, 1999, or amethod analogous thereto. For example, treatment with an acid, a base,reduction, UV, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride, Palladium acetate,etc. can be used.

When the compound (I) is obtained in a free form by the reactiondescribed above, according to a conventional method, it can be convertedinto a salt with an inorganic acid (for example, hydrochloric acid,sulfuric acid, hydrobromic acid and the like), an organic acid (forexample, methanesulfonic acid, benzensulfonic acid, toluenesulfonicacid, oxalic acid, fumaric acid, maleic acid, tartaric acid and thelike), an inorganic base (for example, an alkaline metal such as sodium,potassium and the like, an alkaline earth metal such as calcium,magnesium and the like, aluminum or ammonium) or an organic base (forexample, trimethylamine, triethylamine, pyridine, picoline,ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine orN,N′-dibenzylethylenediamine and the like). When the compound (I) isobtained as a salt, according to a conventional method, it can beconverted into a free form or another salt.

When the starting compound can form a salt in the reaction describedabove, the compound may be used as a salt. As such a salt, there is, forexample, a salt exemplified as a salt of the compound (I).

The compound (I) of the present invention obtained by these methods canbe isolated and purified by a conventional method such as concentration,solvent extraction, recrystallization, distillation, columnchromatography and the like.

When the compound (I) contains an optical isomer, a stereoisomer, aposition isomer or a rotational isomer, these isomers are included inthe compound (I), and can be obtained as an isolated product by asynthesis or separation method known per se (for example, concentration,solvent extraction, column chromatography, recrystallization and thelike). For example when an optical isomer of the compound (I) exists,the optical isomer resolved from the compound is also included in thecompound (I).

The optical isomer can be produced by a method known per se.Specifically, the optical isomer is obtained by using an opticallyactive synthesis intermediate or by optically resolving a racemate ofthe end product according to a conventional method.

As the optical resolution, a method known per se, for example,fractional recrystallization, chiral column procedure, diastereomerprocedure and the like can be used.

1) Fractional Recrystallization

A method for obtaining a free optical isomer, wherein a salt of aracemate is formed with an optically active compound (for example,(+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaricacid, (+)-1-phenethylamine, (−)-1-phenethylamine, cinchonine,(−)-cinchonidine, brucine or the like), which is then separated byfractional recrystallization, if necessary followed by neutralization toobtain the free optical isomers.

2) Chiral Column Method

A method for separating a racemate or a salt by applying it to a columnfor optical isomer separation (chiral column). For example, in case of aliquid chromatography, a mixture of the optical isomers is added to achiral column such as ENANTIO-OVM (manufactured by TOSOH CORPORATION) orCPI COMPANY CHIRAL series manufactured by DAICEL CHEMICAL INDUSTRIES,LTD., and eluted with water, various buffers (e.g., phosphate buffer),organic solvents (e.g., ethanol, methanol, isopropanol, acetonitrile,trifluoroacetic acid, diethylamine and the like) alone or in a mixtureto separate into optical isomers. Alternatively, in case of a gaschromatography, a chiral column such as CP-Chirasil-DeX CB (GL Sciences,Inc.) or the like is used to separate into optical isomers.

3) Diastereomer Method

A method for obtaining an optical isomer, wherein a racemate issubjected to a chemical reaction with an optically active reagent toform a diastereomer mixture, which is then separated into singlesubstances by a conventional method (for example, fractionalrecrystallization, chromatography method and the like), from either ofwhich an optically active reagent portion is cleaved by a chemicaltreatment such as hydrolysis to obtain the desired optical isomer. Forexample, in case where the compound (I) has hydroxy or primary orsecondary amino in its molecule, the compound and an optically activeorganic acid (for example, MTPA[α-methoxy-α-(trifluoromethyl)phenylacetic acid], (−)-menthoxyaceticacid and the like) are subjected to a condensation reaction to obtainthe diastereomers in the forms of esters or amides, respectively. On theother hand, when the compound (I) contains a carboxylate group, thecompound and an optically active amine or alcohol reagent are subjectedto a condensation reaction to obtain the diastereomers in the form ofamides or esters, respectively. The diastereomer separated is convertedinto an optical isomer of the starting compound by subjecting it to acidhydrolysis or basic hydrolysis.

The compound (I) or its salt may be crystals.

The crystals of the compound (I) or its salt (hereinafter sometimesreferred to as the crystals of the present invention) can be produced bysubjecting the compound (I) or its salt to a crystallization methodknown per se to crystallize it.

Examples of the crystallization method include crystallization from asolution, crystallization from vapor, crystallization from a melt andthe like.

As the “crystallization from a solution”, a generally employing methodis to change an unsaturated state to a supersaturated state by alteringa factor involved in the solubility of the compound (solventcomposition, pH, temperature, ion strength, redox conditions and thelike), or an amount of a solvent. Specifically, for example, there areconcentration, gradual cooling, reaction (diffusion, electrolysis),hydrothermal growth, flux method and the like. Examples of the solventto be used include aromatic hydrocarbons (e.g., benzene, toluene, xyleneand the like), halogenated hydrocarbons (e.g., dichloromethane,chloroform and the like), saturated hydrocarbons (e.g., hexane, heptane,cyclohexane and the like), ethers (e.g., diethyl ether, diisopropylether, tetrahydrofuran, dioxane and the like), nitrites (e.g.,acetonitrile and the like), ketones (e.g., acetone and the like),sulfoxides (e.g., dimethyl sulfoxide and the like), acid amides (e.g.,N,N-dimethylformamide and the like), esters (e.g., ethyl acetate and thelike), alcohol (e.g., methanol, ethanol, isopropyl alcohol and thelike), water and the like. These solvents can be used alone or incombination in a suitable ratio (e.g., 1:1 to 1:100 (by volume)).

Examples of the “crystallization from vapor” include a vaporizationmethod (sealed tube method, gas flow method), gas phase reaction method,chemical transportation method and the like.

Examples of the “crystallization from a melt” include a normal freezingmethod (pulling method, temperature gradient method, Bridgeman method),a zone melting method (zone leveling method, float zone method), specialgrowth method (VLS method, liquid phase epitaxy method) and the like.

As the preferred crystallization method, there are a method wherein thecompound (I) or its salt is dissolved in a suitable solvent (e.g., analcohol such as methanol, ethanol, etc.) at a temperature of 20 to 120°C., and the resultant solution is cooled to a temperature below thedissolution temperature (for example, 0 to 50° C., preferably 0 to 20°C.), and the like.

The crystals of the present invention thus obtained can be isolated forexample by filtration or the like.

As used herein, the melting point means that measured with a traceamount melting point meter (Yanaco. LTD. Co., Ltd., model MP-500D) or aDSC (differential scanning calorimeter) device (SEIKO, EXSTAR 6000) andthe like.

Further, as used herein, the peaks in a powder X-ray diffraction methodare those measured with a model RINT 2100 device (RIGAKU DENKI) and thelike by using as a radiation source a Cu—K α1 beam (tube voltage: 40 KV;tube current: 50 mA).

In general, sometimes, the melting point and the powder X-raydiffraction peaks vary depending on the device and measurementconditions. The crystals herein may be those having a melting point andpowder X-ray diffraction peaks which are different from those specifiedherein in so far as they are within an ordinary error range.

The crystals of the present invention are excellent in physicochemicalcharacteristics (e.g., melting point, solubility, stability and thelike) and biological characteristics (e.g., pharmacokinetics(absorption, distribution, metabolism, excretion), manifestation ofpharmacological activity and the like) and is extremely useful as amedicine.

The compound (I) of the present invention or a salt or prodrug thereof(hereinafter sometimes simply referred to as the compound of the presentinvention) has, in addition to an inhibitory effect of an increasingbronchial blood vessel permeability induced by capsicin, excellenttachykinin receptor antagonistic activity, especially substance Preceptor antagonistic activity and neurokinin A receptor antagonisticactivity. The compound of the present invention has low toxicity and issafe.

Accordingly, the compound of the present invention having excellent SPreceptor antagonistic activity, neurokinon A receptor antagonisticactivity, etc. can be used as a safe medicine to a mammal (for example,mouse, rat, hamster, rabbit, cat, dog, cattle, sheep, monkey, human andthe like) in prevention or treatment of various diseases such assubstance P-related diseases, for example, inflammation or allergicdiseases (for example, atopic dermatitis, dermatitis, herpes, psoriasis,asthma, bronchitis, chronic occlusive pulmonary disease, expectoration,rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, multiplesclerosis, conjunctivitis, cystitis and the like), pain, migraine,neuralgia, itching, cough, further central nervous system diseases [forexample, schizophrenia, Parkinson's disease, depression, anxietyneurosis, obsessive-compulsive neurosis, panic disorder, dementia (forexample, Alzheimer's disease and the like) and the like], digestiveorgan diseases [for example, irritative bowel syndrome, ulcerativecolitis, Crohn's disease, urease-positive helical gram negativemicroorganism (for example, Helicobacter pylori and the like)-inducedabnormality (for example, gastiritis, gastric ulcer and the like) andthe like], vomitting, abnormal urination (for example, pollakiuria,incontinence of urine and the like), circulatory diseases (for example,angina pectoris, hypertension, cardiac insufficiency, thrombosis and thelike) and an immune abnormality and the like. In particular, thecompound of the present invention is useful as a tachykinin receptorantagonist, an agent for improving an abnormal urination such aspollakiuria and incontinence of urine as well as an agent for treatingsuch an abnormal urination.

Further, the compound of the present invention is useful as an agent forpreventing or treating depression, anxiety, manic-depressive psychosis,schizophrenia, mania, migraine, cancer, HIV infection, cardiovasculardisorder, solar dermatitis, hypogonadism, ataxia, cognitive disorder orcircadian rhythm disorder.

A pharmaceutical preparation containing the compound of the presentinvention may be any dosage form such as a solid preparation includingpowder, granules, tablet, capsule, suppository and the like as well as aliquid preparation including syrup, emulsion, injectable preparation,suspension and the like.

The pharmaceutical preparation of the present invention can be producedby a conventional method such as mixing, kneading, granulating, tabletcompression, coating, sterilization, emulsification and the likedepending on a particular dosage form of the preparation. For producingthe preparation, for example, respective sections in JapanesePharmacopeia Preparation General Rules can be referred to.

In the pharmaceutical preparation of the present invention, the contentof the compound of the present invention or a salt thereof variesdepending on the dosage form of the preparation but, usually, it isabout 0.01 to 100% by weight, preferably about 0.1 to 50% by weight,more preferably about 0.5 to 20% by weight based on the entire weight ofthe preparation.

When the compound of the present invention is used as the pharmaceuticalpreparation described above, it can be administered orally orparenterally as it is or in a solid dosage form such as a powder, fineparticles, granules, tablet, capsule and the like or in a liquid dosageform such as an injectable preparation which is obtained by mixing witha pharmaceutically acceptable carrier, for example, an excipient (forexample, starch, lactose, sugar, calcium carbonate, calcium phosphateand the like), a binder (for example, starch, gum arabic,carboxymethylcellulose, hydroxypropyl cellulose, crystalline cellulose,arginic acid, gelatin, polyvinyl pyrrolidone and the like), a lubricant(for example, stearic acid, magnesium stearate, calcium stearate, talcand the like), a disintegrant (for example, calciumcarboxymethylcellulose, talc and the like), a diluent (for example,water for injection, physiological saline and the like), if necessary,together with additives (stabilizer, preservative, colorant, flavor,solubilizer, emulsifier, buffer, isotonicity and the like), and thelike, according to a conventional method.

The dose varies depending on the type of the compound of the presentinvention or a pharmaceutically acceptable salt thereof, administrationroute, disease conditions and age of a patient, but a daily oral dose inan adult having an abnormal urination may be, for example, about 0.005to 50 mg, preferably about 0.05 to 10 mg, more preferably about 0.2 to 4mg as the compound of the present invention per kg body weight, whichmay be divided into 1 to 3 times a day.

The compound of the present invention can also be used in combinationwith a suitable amount of another pharmacologically active component byappropriately compounding or using them together.

The combined use of the compound of the present invention and a medicineto be used together results in, for example, the following excellenteffects.

(1) The dose of the compound of the present invention or a medicine tobe used together can be reduced when compared with that when each isadministered alone. More specifically, when the compound of the presentinvention is used together with an anticholinergic agent or an NK-2receptor antagonist, the dose of the anticholinergic agent or the NK-2receptor antagonist becomes lower than that when administered alone,whereby enabling reduction in side effects such as xerostomia, etc.

(2) A medicine to be used together with the compound of the presentinvention can be selected according to the condition (mild, severe,etc.) of a patient.

(3) A medicine to be used together whose functional mechanism isdifferent from that of the compound of the present invention can beselected so that a treatment period becomes longer.

(4) A medicine to be used together whose functional mechanism isdifferent from that of the compound of the present invention can beselected so that a long lasting effect is realized.

(5) A synergistic effect can be obtained by the combined use of thecompound of the present invention and a medicine to be used together.

Examples of the medicine to be compounded or used together with thecompound of the present invention (hereinafter referred a medicine to beused together) include the following agents:

(1) Diabetes Treating Agents

An insulin preparation [e.g., an animal insulin preparation derived frombovine or porcine pancreas; a human insulin preparation synthesized bygene engineering technique using E. coli or yeast; zinc insulin: zincinsulin protamine; an insulin fragment or derivative (e.g., INS-1 etc.)and the like], an insulin sensitivity-enhancing agent (e.g.,pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate,JTT-501, MCC-555, YM-440, GI-262570, KRP-297, FK-614, CS-011 and thelike), an α-glycosidase inhibitor (e.g., voglibose, acarbose, miglitol,emiglitate and the like), a biganide agent (e.g., fenformin, metformin,buformin and the like), or a sulfonylurea agent (e.g., tolbutamid,glibenclamid, gliclazide, chlorpropamide, tolazamide, acetohexamide,glyclopyramide, glimepiride and the like), or other insulinsecretion-promoting agents (e.g., repaglinide, senaglinide, mitiglinideor its calcium salt hydrate, GLP-1, nateglinide and the like), adipeptyl peptidase IV inhibitor (e.g., NVP-DPP-278, PT-100, P32/98 andthe like), a β3 agonist (e.g., CL-316243, SR-58611-A, UL-TG-307,AJ-9677, AZ40140 and the like), an amylin agonist (e.g., pramlintide andthe like), a phosphotyrosine phosphatase inhibitor (e.g., vanadic acidand the like), a gluconeogenesis inhibitor (e.g., glycogen phosphorylaseinhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist and thelike), SGLT (sodium-glucose cotransporter) inhibitor (e.g., T-1095 andthe like), and the like.

(2) Diabetic Complication Treating Agent

An aldose reductase inhibitor (e.g., tolrestat, epalrestat, zenarestat,zopolrestat, fidarestat (SK-860), minalrestat (ARI-509), CT-112 and thelike), a neurotrophic factor (e.g., NGF, NT-3 and the like), an AGEinhibitor (e.g., ALT-945, Pimagedine, pyratoxathine,N-phenacylthiazolium bromide (ALT-766), EXO-226 and the like), an activeoxygen scavenger (e.g., thioctic acid), a cerebrovascular dilator (e.g.,thiopride and the like) and the like.

(3) Antihyperlipidemic Agent

A statin compound which is a cholesterol synthesis inhibitor (e.g.,pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin,serivastatin or its salt (e.g., sodium salt, etc.) and the like), asqualene synthesis inhibiting- or triglyceride reducing-fibrate compound(e.g., bezafibrate, clofibrate, simfibrate, clinofibrate and the like),and the like.

(4) Hypotensive Agent

An angiotensin converting enzyme inhibitor (e.g., captopril, enalapril,delapril and the like) or an angiotensin II antagonist (e.g., losartan,candesartan cilexetil and the like), a calcium antagonist (e.g.,manidipine, nifedipine, amlodin, efonidipine, nicardipine and the like),clonidine, and the like.

(5) Anti-Obesic

A central anti-obesic agent (e.g., dexfenfluramine, fenfluramine,phentermine, sibutramine, amfepramone, dexamphetamine, mazindol,phenylpropanolamine, clobenzorex and the like), a pancreatic lipaseinhibitor (e.g., orlistat and the like), a β3 agonist (e.g., CL-316243,SR-58611-A, UL-TG-307, AJ-9677, AZ40140 and the like), a peptidicappetite-suppressing agent (e.g., leptin, CNTF (ciliary neurotrophicfactor) and the like), a cholecystokinin agonist (e.g., rinchitript,FPL-15849 and the like) and the like.

(6) Diuretic

A xanthine derivative (e.g., teobromine sodium salicylate, teobrominecalcium salicylate and the like), a thiazide preparation (e.g.,ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide,hydroflumethiazide, benzylhydrochlorothiazide, penflutizide,polythiazide, methyclothiazide and the like), an anti-aldosteronepreparation (e.g., spironolactone, triamterene and the like), acarbonate dehydrogenase inhibitor (e.g., acetazolamide and the like), achlorbenzensulfonamide preparation (e.g., chlorthalidone, mefruside,indapamide and the like), azosemide, isosorbide, ethacrynic acid,piretanide, bumetanide furosemide and the like.

(7) Chemotherapeutic Agent

An alkylating agent (e.g., cyclophosphamide, iphosphamide and the like),a metabolism antagonist (e.g., methotrexate, 5-fluorouracil and thelike), an anticancer antibiotic (e.g., mitomycin, adriamycin and thelike), a plant derived anticancer agent (e.g., vincristine, vindesine,taxol and the like), cisplatin, carboplatin, ethopoxide and the like,with 5-fluorouracil derivatives such as furtulon or neo furtulon beingpreferred.

(8) Immunotherapeutic Agent

A microbial or bacterial component (e.g., muramyldipeptide derivative,picibanil and the like), an immunoenhancing polysaccharide (e.g.,lentinan, schizophyllan, krestin and the like), a cytokine obtained bygene engineering technique (e.g., interferon, interleukin (IL) and thelike), a colony stimulating factor (e.g., granulocyte colony stimulatingfactor, erythropoietin and the like), and the like with IL-1, IL-2 andIL-12 being preferred.

(9) Agent Proven in Animal Model or Clinically to Have CachexiaImproving Activity

A progesterone derivative (e.g., megesterol acetate) [Journal ofClinical Oncology, Vol. 12, p. 213-225, 1994], a metoclopramide agent, atetrahydrocannabinol agent [ibid], a fat metabolism-improving agent(e.g., eicosapentaenoic acid and the like) [British Journal of Cancer,Vol. 68, p. 314-318, 1993], a growth hormone, IGF-1, an antibody againsta cachexia-inducing factor such as TNF-α, LIF, IL-6, or oncostatin M,and the like.

(10) Anti-Inflammatory

A steroid agent (e.g., dexamethasone and the like), sodium hyaluronate,a cyclooxygenase inhibitor (e.g., indomethacin, ketoprofen, loxoprofen,meloxicam, ampiroxicam, celecoxib, rofecoxib and the like), and thelike.

(11) Others

A glycosylation inhibitor (e.g., ALT-711 and the like), a neuranagenesispromoter (e.g., Y-128, VX853, prosaptide and the like), a CNS agonist(e.g., anti-depressant such as desipramine, amitriptyline, imipramine,floxetine, paroxetine, doxepin, carbamazepine and the like), ananti-epileptic agent (e.g., lamotrigine), an anti-arrhythmic agent(e.g., mexiletine), an acetylcholine receptor ligand (e.g., ABT-594), anendothelin receptor antagonist (e.g., ABT-627), a monoamine intakeinhibitor (e.g., tramadol), an indoleamine intake inhibitor (e.g.,fluoxetine, paroxetine), an opioid analgesic (e.g., morphine), a GABAreceptor agonist (e.g., gabapentin), a GABA intake inhibitor (e.g.,tiagabin), an α₂ receptor agonist (e.g., clonidine), a local anesthesia(e.g., capsicin), a protein kinase C inhibitor (e.g., LY-333531), ananxiolytic agent (e.g., benzodiazepines), a phosphodiesterase inhibitor(e.g., sildenafil), a dopamine receptor agonist (e.g., apomorphine), ananti-cholinergic agent, an α₁ receptor blocker (e.g., tamusulosin), amuscle relaxant (e.g., baclofen), a potassium channel opener (e.g.,nicorandil), a calcium channel blocker (e.g., nifedipine), anAlzheimer's disease preventing and treating agent (e.g., donepezil,rivastigmine, galanthamine), a Parkinson's disease treating agent (e.g.,L-dopa), an antithrombotic agent (e.g., aspirin, cilostazol), an NK-2receptor antagonist, an HIV infection treating agent (saquinavir,zidovudine, lamivudine, nevirapine), a chronic obstructive pulmonarydisease treating agent (salmeterol, tiotropium bromide, silomirasut) andthe like.

Examples of the anticholinergic agent include atropin, scopolamin,homatropine, tropicamido, cyclopentorate, butylscopolamin bromide,propantheline bromide, methylbenactyzium bromide, mepenzolate bromide,flavoxate, pirenzepine, ipratropium bromide, trihexyphenidyl,oxybutynin, propiverine, darifenacin, tolterodine, temiverine, trospiumchloride or its salt (e.g., atropin sulfate, scopolamine hydrobromide,homatropine hydrobromide, cyclopentorate hydrochloride, flavoxatehydrochloride, pirenzepine hydrochloride, trihexyphenidyl hydrochloride,oxybutynin chloride, tolterodine, tartarate and the like), withoxybutynin, propiverine, darifenacin , tolterodine, temiverine, trospiumchloride or its salt (e.g., oxybutynin chloride, tolterodine tartarate)being preferred. An acetylcholine esterase inhibitor (e.g., distigmineand the like) may also be used.

Examples of the NK-2 receptor antagonist include GR94800, GR159897,MEN10627, MEN11420 (nepadutant), SR144190, SR48968 (saredutant) or saltsthereof.

The pharmaceutical compositions for the combined used of the compound ofthe present invention and a medicine to be used together includes any of(1) a pharmaceutical composition comprising the compound of the presentinvention and a medicine to be used together, and (2) separatelyprepared preparations of the compound of the present invention and amedicine to be used together. Hereinafter, they are abbreviated as thecombination preparations of the present invention.

The combination preparations of the present invention can beadministered orally or parenterally in the form of, for example, solidpreparations such as powders, granules, tablets, capsules and the like,liquid preparations such as syrups, emulsions, injectable preparations(including subcutaneous injection, intravenous injection, intramuscularinjection and dripping infusion) and the like, sustained-releasepreparations such as subliqual tablets, buccal tablets, troches,microcapsules and the like, oral quick disintegrating preparations, aswell as suppositories, which are obtained by using the effectivecomponents of the compound of the present invention and a medicine to beused together as they are or mixing them with a pharmaceuticallyacceptable carrier separately or simultaneously.

As the above pharmaceutically acceptable carrier, various conventionalorganic and inorganic carrier materials to be used as pharmaceutical rawmaterials are used. They are compounded as excipients, lubricants,binders and disintegrants in solid preparations, solvents, dissolutionaids, suspending agents, isotonicities, buffering agents and soothingagents in liquid preparations, and the like. Furthermore, if necessary,other additives such as preservatives, antioxidants, colorants,sweeteners can also be used.

Preferred examples of the above excipient include lactose, sugar,D-mannitol, starch, crystalline cellulose, light silicic anhydride,calcium carbonate, calcium phosphate and the like.

Preferred examples of the above lubricant include stearic acid,magnesium stearate, calcium stearate, talc, colloidal silica and thelike.

Preferred examples of the above binder include crystalline cellulose,sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinyl pyrrolidone, gum arabic, gelatin and the like.

Preferred examples of the above disintegrant include starch,carboxymethylcellulose, calcium carboxymethylcellulose, sodiumcroscarmellose, sodium carboxymethyl starch and the like.

Preferred examples of the above solvent include water for injection,physiological saline, alcohol, propylene glycol, macrogol, sesame oil,corn oil and the like.

Preferred examples of the above dissolution aid include polyethyleneglycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate and the like.

Preferred examples of the above suspending agent include surfactantssuch as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethoniumchloride, glycerin monostearate and the like; hydrophilic polymers suchas polyvinyl alcohol, polyvinyl pyrrolidone, sodiumcarboxymethylcellulose, methylcellulose, hydroxymethyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose and the like.

Preferred examples of the above isotonicity include sodium chloride,glycerin, D-mannitol and the like.

Preferred examples of the above buffering agent include a buffersolution of phosphate, acetate, carbonate, citrate and the like.

Preferred examples of the above soothing agent include benzyl alcoholand the like.

Preferred examples of the above preservative include p-hydroxy benzoateesters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroaceticacid, sorbic acid and the like.

Preferred examples of the above antioxidant include sulfite, ascorbicacid and the like.

These preparations can be produced by a method known per se which isgenerally employed in production steps of a pharmaceutical preparation.

For example, the compound of the present invention or a medicine to beused together can be prepared in the form of an injectable preparationby compounding it with a dispersant (e.g., Tween 80 (manufactured byATLAS POWDER, USA), HCO60 (manufactured by NIKKO CHEMICALS),polyethylene glycol, carboxymethylcellulose, sodium alginate,hydroxypropylmethyl cellulose, dextrin and the like), a stabilizer(e.g., ascorbic acid, sodium pyrosulfite), a surfactant (e.g.,polysorbate 80, macrogol and the like), a solubilizing agent (e.g.,glycerin, ethanol and the like), a buffering agent (e.g., phosphoricacid or its alkali metal salt, citric acid or its alkali metal salt, andthe like), an isotonicity (e.g., sodium chloride, potassium chloride,mannitol, sorbitol, glucose and the like), a pH adjuster (e.g.,hydrochloric acid, sodium hydroxide and the like), a preservative (e.g.,ethyl p-oxybenzoate, benzoic acid, methylparabene, propylparabene,benzyl alcohol and the like), a solubilizer (e.g., concentratedglycerin, meglumine and the like), a solubilizing aid (e.g., propyleneglycol, sugar and the like), a soothing agent (e.g., glucose, benzylalcohol and the like) and the like to obtain an aqueous injectablepreparation, or dissolving, suspending or emulsifying in a vegetable oilsuch as olive oil, sesame oil, cottonseed oil, corn oil or the like, orin a solubilizing aid such as propylene glycol or the like to obtain anoily injectable preparation.

In order to obtain an oral dosage preparation, according to a methodknown per se, the compound of the present invention or a medicine to beused together is subjected to compression molding, for example, withaddition of an excipient (e.g., lactose, sugar, starch and the like), adisintegrant (e.g., starch, calcium carbonate and the like), a binder(e.g., starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose and the like) or a lublicant (e.g.,talc, magnesium stearate, polyethylene glycol 6000 and the like) and thelike, if necessary, followed by subjecting to taste masking, and coatingfor entric property or long lasting by a method per se known to obtainthe oral dosage preparation. Examples of the coating agent to be usedinclude hydroxypropylmethyl cellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80,Pluronic F68, cellulose acetate phthalate, hydroxypropylmethyl cellulosephthalate, hydroxymethyl cellulose acetate succinate, Eudragit(methacrylic acid/acrylic acid copolymer manufactured by Rohm, German),a colorant (e.g., colcothar, titanium dioxide and the like) and thelike. The oral dosage preparation may be any of a quick-releasepreparation and a sustained-release preparation.

For example, in order to obtain a suppository, according to a methodknown per se, the compound of the present invention or a medicine to beused together can be formulated in the form of an oily or aqueous solid,semi-solid or liquid suppository. Examples of an oily substrate to beused in the above composition include a higher fatty acid glyceride[e.g., cocoa butter, witepsols (manufactured by Dynamit Nobel,Germany)], a medium fatty acid [e.g., miglyol (manufactured by DynamitNobel, Germany) and the like], or a vegetable oil (e.g., sesame oil,soybean oil, cottonseed oil and the like). Examples of an aqueoussubstrate include polyethylene glycol and propylene glycol, and examplesof an aqueous gel substrate include natural gums, cellulose derivatives,vinyl polymers, acrylic acid polymers and the like.

Examples of the above sustained-release preparation includesustained-release microcapsules and the like.

While sustained-release microcapsules can be obtained by a method knownper se, preferably, a sustained-release preparation is prepared, forexample, by the method of [2] hereinafter and administered.

Preferably, the compound of the present invention is formulated as anoral dosage preparation such as a solid preparation (e.g., powder,granules, tablet, capsule) or a rectal dosage preparation such as asuppository. An oral dosage preparation is especially preferred.

A medicine to be used together can be formulated in the above dosageform depending on the kind of the medicine.

Hereinafter, [1] an injectable preparation of the compound of thepresent invention or a medicine to be used together and its production,[2] a sustained-release or quick-release preparation of the compound ofthe present invention or a medicine to be used together and itsproduction and [3] a sublingual, buccal or oral quick disintegratingpreparations of the compound of the present invention or a medicine tobe used together and its production will be specifically illustrated.

[1] Injectable Preparation and its Production

An injectable preparation obtained by dissolving the compound of thepresent invention or a medicine to be used together in water ispreferred. The injectable preparation may contain a benzoate and/or asalicylate.

The injectable preparation is obtained by dissolving the compound of thepresent invention or a medicine to be used together and optionally abenzoate and/or a salicylate in water.

Examples of the above benzoate and/or salicylate include an alkali metalsalt such as sodium and potassium salts, an alkaline earth metal saltsuch as calcium and magnesium salts, an ammonium salt, a meglumine salt,a salt of an organic acid such as trometamol, and the like.

The concentration of the compound of the present invention or a medicineto be used together in the injectable preparation is about 0.5 to 50 w/v%, preferably about 3 to 20 w/v %. The concentration of a benzoateand/or a salicylate is 0.5 to 50 w/v %, preferably 3 to 20 w/v %.

Further, additives generally used in an injectable preparation such as astabilizer (ascorbic acid, sodium pyrosulfite and the like), asurfactant (polysorbate 80, macrogol and the like), a solubilizing agent(glycerin, ethanol and the like), a buffering agent (phosphoric acid andits alkali metal salt, citric acid and its alkali metal salt and thelike), an isotonicity (sodium chloride, potassium chloride and thelike), a dispersing agent (hydroxypropylmethyl cellulose, dextrin), a pHadjuster (hydrochloric acid, sodium hydroxide and the like), apreservative (ethyl p-oxybenzoate, benzoic acid and the like), asolubilizer (concentrated glycerin, meglumine and the like), asolubilizing aid (propylene glycol, sugar and the like), a soothingagent (glucose, benzyl alcohol and the like) are appropriately added tothe preparation. Any of these additives is added in an amount generallyused in an injectable preparation.

The pH of the injectable preparation is adjusted to 2 to 12, preferably2.5 to 8.0 with addition of a pH adjuster.

The injectable preparation is obtained by dissolving the compound of thepresent invention or a medicine to be used together, optionally abenzoate and/or salicylate, and, if necessary, the above additives inwater. These components may be dissolved in any order according to thesame manner as that for producing a conventional injectable preparation.

An injectable aqueous solution is preferably warmed, and used as aninjectable preparation after sterilization by filtration or autoclavedaccording to the same manner as that of a conventional injectablepreparation.

An aqueous injectable preparation is preferably autoclaved at 100 to121° C. for 5 to 30 minutes.

Further, the preparation may be a solution to which antibacterialactivity is given so that it can be divided to administer plural times.

[2] Sustained-Release or Quick-Release Preparation and its Production

A sustained-release preparation comprising a core containing thecompound of the present invention or a medicine to be used togetherwhich is optionally coated with a water-insoluble material or a swellingpolymer is preferred. For example, a sustained-release oral preparationin a single daily dosage form is preferred.

Examples of the water-insoluble material used for the coating agentinclude cellulose ethers such as ethyl cellulose, butyl cellulose andthe like, cellulose esters such as cellulose acetate, cellulosepropionate and the like, polyvinyl esters such as polyvinyl acetate,polyvinyl butyrate and the like, acrylic acid polymers such as anacrylic acid/methacrylic acid copolymer, a methyl methacrylatecopolymer, an ethoxyethyl methacrylate/cinnamoethylmethacrylate/aminoalkyl methacrylate copolymer, a polyacrylic acid, apolymethacrylic acid, a methacrylic acid alkylamide copolymer, apoly(methyl methacrylate), a polymethacrylate, an aminoalkylmethacrylate copolymer, a poly(methacrylic anhydride), a glycidylmethacrylate copolymer, in particular, a series of Eudragits (Rohm &Pharma) such as Eudragit RS-100, RL-100, RS-30D, RL-30D, RL-PO, RS-PO(ethyl acrylate/methyl methacrylate/chlorotrimethyl methacrylate/ethylammonium copolymer) and Eudragit NE-30D (methyl methacrylate/ethylacrylate copolymer) and the like, hydrogenated oils such as hydrogenatedcastor oil (e.g., LUBRI WAX (Freund Industrial Co., Ltd.) and the like),waxes such as carnauba wax, a fatty acid glycerin ester, paraffin andthe like, polyglycerin fatty acid esters, and the like.

The swelling polymer is preferably a polymer having an acidic cleavablegroup and exhibiting pH-dependent swelling, and a polymer having anacidic cleavable group which undergoes a less swelling at acidic pH suchas in the stomach but is swollen extensively at neutral pH such as insmall and large intestines is preferred.

Examples of such a polymer having an acidic cleavable group andexhibiting pH-dependent swelling include a crosslinked polyacrylic acidpolymer such as Carbomers 934P, 940, 941, 974P, 980, 1342 and the like,polycarbophil and calcium polycarbophil (all manufactured by BF GoodrichChemicals), Hivis Wakos 103, 104, 105 and 304 (all manufactured by WakoPure Chemical Industries, Ltd.), and the like.

The coating agent used in the sustained-release preparation may furthercontain a hydrophilic material.

Examples of the hydrophilic material include a polysaccharide which mayhave a sulfate group such as pullulan, dextrin, alkali metal alginatesand the like, a polysaccharide having a hydroxyalkyl group or acarboxyalkyl group such as hydroxypropyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and the like, methyl cellulose,polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol and thelike.

The water-insoluble material content in the coating agent of thesustained-release preparation is about 30 to about 90% (w/w), preferablyabout 35 to about 80% (w/w), more preferably about 40 to about 75%(w/w), and the swelling polymer content is about 3 to about 30% (w/w),preferably about 3 to about 15% (w/w). The coating agent may furthercontain the hydrophilic material, the content of which in the coatingagent is about 50% (w/w) or less, preferably about 5 to about 40% (w/w),more preferably about 5 to about 35% (w/w). As used herein, the above %(w/w) means a % by weight based on the coating agent composition whichis the remainder of the coating agent solution after removing anysolvent (e.g., water, a lower alcohol such as methanol, ethanol and thelike).

The sustained-release preparation is produced by preparing a corecontaining a drug as exemplified hereinafter, followed by coating theresultant core with a coating agent solution obtained by heat-melting awater-insoluble material or a swelling polymer or by dissolving ordispersing such a material in a solvent.

I. Preparation of Core Containing Drug

While the shape of a core containing a drug to be coated with a coatingagent (hereinafter sometimes simply referred to as a core) is notspecifically limited, preferably, it is prepared in the shape ofparticles such as granules, fine particles or the like.

When the core is granules or fine particles, they have a mean particlesize of preferably about 150 to 2,000 μm, more preferably about 500 to1,400 μm.

The core can be prepared by a conventional method. For example, a drugis mixed with a suitable excipient, binder, disintegrant, lubricant,stabilizer and the like, and then subjected to wet extrudinggranulation, fluidized bed granulation or the like.

The drug content in the core is about 0.5 to about 95% (w/w), preferablyabout 5.0 to about 80% (w/w), more preferably about 30 to about 70%(w/w).

Examples of the excipient contained in the core include a saccharidesuch as sugar, lactose, mannitol, glucose, and the like, starch,crystalline cellulose, calcium phosphate, corn starch and the like.Among them, crystalline cellulose and corn starch are preferred.

Examples of the binder to be used include polyvinyl alcohol,hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone,Pluronic F68, gum arabic, gelatin, starch and the like. Examples of thedisintegrant include calcium carboxymethyl cellulose (ECG505), sodiumcroscarmellose (Ac-Di-Sol), crosslinked polyvinyl pyrrolidone(crospovidone), a low substituted hydroxypropyl cellulose (L-HPC) andthe like. Among them, hydroxypropyl cellulose, polyvinyl pyrrolidone anda low substituted hydroxypropyl cellulose are preferred. Examples of thelubricant and the anticoagulant include talc, magnesium stearate and itsinorganic salts, and examples of the glidant include polyethylene glycoland the like. Examples of the stabilizer include an acid such astartaric acid, citric acid, succinic acid, fumaric acid, maleic acid andthe like.

In addition to the method described above, the core can be prepared byusing other methods such as an agitating granulation method, a pancoating method, a fluidized bed coating method and a melt coolinggranulation method, wherein a drug or a mixture thereof with anexcipient, a lublicant and the like is added to inert carrier particlesas seeds for the core by portions with spraying a binder dissolved in asuitable solvent such as water, a lower alcohol (e.g., methanol,ethanol, etc.) or the like. Examples of the inert carrier particlesinclude those prepared from sugar, lactose, starch, crystallinecellulose and waxes, and, preferably, they have a mean particle size ofabout 100 μm to about 1,500 μm.

In order to separate the drug contained in the core from a coatingagent, the surface of the core may be covered with a protectivematerial. Examples of the protective material include the abovehydrophilic material and water-insoluble material. The preferredprotective material is polyethylene glycol or a polysaccharide having ahydroxyalkyl group or a carboxyalkyl group, more preferably,hydroxypropylmethyl cellulose and hydroxypropyl cellulose. Theprotective material may contain, as a stabilizer, an acid such astartaric acid, citric acid, succinic acid, fumaric acid, maleic acid andthe like, and a glidant such as talc. When the protective material isused, the amount thereof to be coated is about 1 to about 15% (w/w),preferably about 1 to about 10% (w/w), more preferably about 2 to about8% (w/w) based on the core.

The protective material can be coated by a conventional coating methodand, specifically, the core is spray-coated with the protective materialby a fluidized bed coating method, a pan coating method and the like.

II. Coating of Core with Coating Agent

The core obtained as described in the above I is coated with a coatingagent solution prepared by melt-heating the above water-insolublematerial, pH-dependent swelling polymer and hydrophilic material ordissolving or dispersing them in a solvent to obtain a sustained-releasepreparation.

As a coating method of the core with the coating agent solution, thereare, for example, spray coating and the like.

The composition ratio of the water-insoluble material, swelling polymerand hydrophilic material in the coating agent solution can be selectedappropriately so that contents of the respective components in thecoating become the above contents.

The amount of the coating agent is about 1 to about 90% (w/w),preferably about 5 to about 50% (w/w), more preferably about 5 to about35% (w/w) based on the core (excluding the protective material coating).

As the solvent for the coating agent solution, water and an organicsolvent can be used alone or as a mixture thereof. When using a mixture,the ratio of water and the organic solvent (water/organic solvent:weight ratio) may vary from 1 to 100%, and is preferably 1 to about 30%.While the organic solvent is not specifically limited in so far as itcan dissolve the water-insoluble material, examples thereof include alower alcohol such as methyl alcohol, ethyl alcohol, isopropyl alcohol,n-butyl alcohol and the like, a lower alkanone such as acetone,acetonitrile, chloroform, methylene chloride and the like. Among them, alower alcohol is preferred, with ethyl alcohol and isopropyl alcoholbeing especially preferred. Water and a mixture of water and an organicsolvent are used preferably as solvents for the coating agent solution.In this case, if necessary, an acid such as tartaric acid, citric acid,succinic acid, fumaric acid, maleic acid and the like may be added tothe coating agent solution for the purpose of stabilizing the coatingagent solution.

As the operation for carrying out the coating by spray coating, aconventional coating method can be used. Specifically, the core issprayed with a coating agent solution by a fluidized bed coating method,a pan coating method or the like. At this time, a lubricant such astalc, titanium oxide, magnesium stearate, calcium stearate light silicicanhydride, etc., and a plasticizer such as glycerin fatty ester,hardened castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol,etc. may also be added.

After coating with a coating agent, an antistatic agent such as talc mayalso be admixed, if necessary.

The quick-release preparation may be a liquid (solution, suspension,emulsion and the like) or a solid (particles, pill, tablet and thelike). While an oral preparation and a parenteral preparation such as aninjectable preparation may be used, an oral preparation is preferred.

The quick-release preparation may usually contain, a carrier, additivesand an excipient (hereinafter sometimes abbreviated as excipients) whichare conventionally used in the pharmaceutical field, in addition to adrug which is an active ingredient. The pharmaceutical excipients arenot specifically limited in so far as it is conventional excipients usedin the pharmaceutical field. Examples of the excipient for an oral solidpreparation include lactose, starch, corn starch, crystalline cellulose(Avicel PH101 manufactured by Asahi Kasei Corporation, and the like),powdered sugar, granulated sugar, mannitol, light silicic anhydride,magnesium carbonate, calcium carbonate, L-cysteine and the like, withcorn starch and mannitol being preferred. Any of these excipients may beemployed alone or in combination with each other. The amounts of theexcipients are, for example, about 4.5 to about 99.4 w/w %, preferablyabout 20 to about 98.5 w/w %, more preferably about 30 to about 97 w/w%, based on the total weight of the quick-release preparation.

The drug content in the quick-release preparation can be appropriatelyselected within the range from about 0.5 to about 95%, preferably about1 to about 60%, based on the total weight of the quick-releasepreparation.

When the quick-release preparation is an oral solid preparation, itcontains a disintegrant in addition to the components described above.Examples of the disintegrant include calcium carboxymethylcellulose(ECG505 manufactured by GOTOKU CHEMICAL COMPANY LTD.), sodiumcroscarmellose (for example, Ac-Di-Sol manufactured by Asahi KaseiCorporation), crospovidone (for example, COLIDON CL manufactured byBASF), low-substituted hydroxypropyl cellulose (Shin-Etsu chemical Co.,Ltd.), carboxymethyl starch (MATSUTANI CHEMICAL INDUSTRY CO., LTD.),sodium carboxymethyl starch (EXORITAB manufactured by KIMURA SANGYO),partial α starch (PCS manufactured by Asahi Kasei Corporation) and thelike. For example, one which disintegrates granules by water absorptionor swelling on contact with water, or forming a channel between anactive component which composes the core and an excipient can be used.Any of these disintegrants can be used alone or in combination with eachother. While the amount of the disintegrant to be used can beappropriately selected according to the type and the amount of the drugto be used or a particular preparation design for the intended releaseperformance, for example, it is about 0.05 to about 30 w/w %, preferablyabout 0.5 to about 15 w/w % based on the total weight of thequick-release preparation.

When the quick-release preparation is an oral solid quick-releasepreparation, it optionally contains additives conventionally used in asolid preparation in addition to the components described above.Examples of the additives include binders (for example, sucrose,gelatin, powdery gum arabic, methyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, carboxymethylcellulose, polyvinylpyrrolidone, pullran, dextrin and the like), lubricants (polyethyleneglycol, magnesium stearate, talc, light silicic anhydride (for example,aerosil (NIPPON AEROSIL)), surfactants (for example, anionic surfactantssuch as sodium alkylsulfate, nonionic surfactants such aspolyoxyethylene fatty ester, polyoxyethylene sorbitan fatty ester,polyoxyethylene castor oil derivatives and the like), colorants (forexample, tar colorants, caramel, colcothar, titanium oxide,riboflavins), if necessary, corrigents (for example, sweeteners, flavorsand the like), adsorbents, preservatives, wetting agents, antistaticagents and the like. Further, as a stabilizer, an organic acid such astartaric acid, citric acid, succinic acid, fumaric acid or the like canalso be added.

As the above binder, hydroxypropyl cellulose, polyethylene glycol andpolyvinyl pyrrolidone and the like are preferably used.

The quick-release preparation can be prepared by mixing the componentsdescribed above and kneading the resultant if necessary and then moldingaccording to a conventional production method. The above mixing can becarried out by a generally employed method, such as mixing and kneading.Specifically, when the quick-release preparation is in the form ofparticles, it can be prepared by mixing components with a verticalgranulator, a multi-purpose kneader (HATA IRON WORKS CO., LTD), afluidized bed granulator FD-5S (POWREX CORPORATION) or thee like, andthen granulating the resultant by wet extrusion granulation or fluidizedbed granulation according to a method similar to that for preparing thecore of the sustained-release preparation described above.

The quick-release preparation and the sustained-release preparation thusobtained as they are or together with appropriate pharmaceuticalexcipients can be compounded in pharmaceutical preparations separatelyby a conventional method to prepare preparations for administering incombination with each other simultaneously or at suitable intervals.Alternatively, both may be compounded in a single oral dosage form(e.g., granules, fine particles, tablet, capsule) as they are ortogether with appropriate pharmaceutical excipients. Both preparationsin the form of granules or fine particles may also be filled in a singlecapsule for oral administration.

[3] Sublingual, Buccal or Oral Quick Disintegration Preparation and itsProduction

A sublingual, buccal or oral quick disintegration preparation may be asolid preparation such as a tablet, or may be a oral mucosa plaster(film).

The sublingual, buccal or oral quick disintegration preparation ispreferably that containing a medicine to be used together and anexcipient. It may also contain auxiliary agents such as a lubricant, anisotonicity, a hydrophilic carrier, a water-dispersible polymer, astabilizer and the like. Further, for the purpose of promoting theabsorption and enhancing the bioavailability, it may also containβ-cyclodextrin or β-cyclodextrin derivatives (e.g.,hydroxypropyl-β-cyclodextrin and the like).

Examples of the above excipient include lactose, sugar, D-mannitol,starch, crystalline cellulose, light silicic anhydride and the like.Examples of the lubricant include magnesium stearate, calcium stearate,talc, colloidal silica and the like, with magnesium stearate andcolloidal silica being preferred. Examples of the isotonicity includesodium chloride, glucose, fructose, mannitol, sorbitol, lactose,saccharose, glycerin and urea, with mannitol being preferred especially.As the hydrophilic carrier, there are, for example, a swellinghydrophilic carrier such as crystalline cellulose, ethyl cellulose,crosslinked polyvinyl pyrrolidone, light silicic anhydride, silicicacid, dicalcium phosphate, calcium carbonate and the like, withcrystalline cellulose (e.g., microcrystalline cellulose and the like)being preferred. As the water-dispersible polymer, there are, forexample, a gum (e.g., tragacanth gum, acacia gum, guar gum), alginate(e.g., sodium alginate), cellulose derivatives (e.g., methyl cellulose,carboxymethylcellulose, hydroxymethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose), gelatin, water-solublestarch, polyacrylic acid (e.g., carbomer), polymethacrylic acid,polyvinyl alcohol, polyethylene glycol, polyvinyl pyrrolidone,polycarbophil, ascorbate palmitate salt and the like, withhydroxypropylmethyl cellulose, polyacrylic acid, alginate, gelatin,carboxymethylcellulose, polyvinyl pyrrolidone and polyethylene glycolbeing preferred. Hydroxypropylmethyl cellulose is especially preferred.As the stabilizer, there are, for example, cysteine, thiosorbitol,tartatic acid, citric acid, sodium carbonate, ascrobic acid, glycine,sodium sulfite and the like, with citric acid and ascorbic acid beingpreferred especially.

The sublingual, buccal or oral quick disintegration preparation can beproduced by mixing the compound of the present invention or a medicineto be used together and an excipient by a method known per se. Further,if desired, the auxiliary agents described above, such as the lubricant,isotonicity, hydrophilic carrier, water-dispersible polymer, stabilizer,colorant, sweetener, preservative and the like may also be admixed.After mixing the components described above simultaneously or at certaintime intervals, the mixture is compressed into tablets to obtain thesublingual, buccal or oral quick disintegration tablet. For the purposeof obtaining a suitable hardness, a solvent such as water and an alcoholcan be used to moisturize or wet the components before or aftertabletting, followed by drying.

When the oral mucosa plaster (film) is prepared, the compound of thepresent invention or a medicine to be used together and the abovewater-dispersible polymer (preferably, hydroxypropyl cellulose,hydroxypropylmethyl cellulose), excipient and the like are dissolved ina solvent such as water, and then the resultant solution is cast into afilm. Further, additives such as a plasticizer, a stabilizer, anantioxidant, a preservative, a colorant, a buffering agent, a sweetenersand the like may be added. A glycol such as polyethylene glycol orpropylene glycol may be added for the purpose of imparting a film withan appropriate elasticity, and a bioadhesive polymer (e.g.,polycarbophile, carbopol) may be added for the purpose of enhancing theadhesion of the film to the oral mucosal lining. The casting can becarried out by pouring a solution onto a non-adhesive surface, spreadingthe solution using a coater such as a doctor blade in a uniformthickness (preferably about 10 to 1000 microns), and then drying thesolution to form a film. The film thus formed is dried at roomtemperature or with warming, and then cut into pieces each having adesired surface area.

As the preferred oral quick disintegration preparation, there is, forexample, a quick diffusion preparation in the form of a solid networkcomprising the compound of the present invention or a medicine to beused together and a water-soluble or water-diffusible carrier which isinert to the compound of the present invention or the medicine to beused together. The network is obtained by sublimating a solvent from asolid composition comprising a solution of the compound of the presentinvention or a medicine to be used together in a suitable solvent.

In addition to the compound of the present invention or a medicine to beused together, preferably, the composition of the oral quickdisintegration preparation further contains a matrix-forming agent and asecondary component.

Examples of the matrix-forming agent include gelatins, dextrins andanimal or vegetable proteins such as soybean, wheat and psyllium seedproteins, and the like; gummy materials such as gum arabic, guar gum,agar, xanthane gum and the like; polysaccharides; alginates;carboxymethylcelluloses; carrageenans; dextrans; pectins; syntheticpolymers such as polyvinyl pyrrolidones; materials derived fromgelatin-gum arabic complexes and the like. Further, also included aresaccharides such as mannitol, dextrose, lactose, galactose, trehaloseand the like; cyclic saccharides such as cyclodextrins and the like;inorganic salts such as sodium phosphate, sodium chloride, aluminumsilicate and the like; amino acids having 2 to 12 carbon atoms such asglycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline,L-isoleucine, L-leucine, L-phenylalanine and the like.

One or more matrix-forming agents can be introduced into a solution orsuspension before solidification. The matrix-forming agents may bepresent in addition to a surfactant, or may be present in the absence ofa surfactant. The matrix-forming agents serve not only to form a matrixitself, but also to aid in maintaining diffusion of the compound of thepresent invention or a medicine to be used together in the solution orsuspension.

The composition may contain a secondary component such as apreservative, an antioxidant, a surfactant, a thickening agent, acolorant, pH adjuster, a flavor, a sweetener, a taste masking agent andthe like. As the suitable colorant, there are, for example, iron oxidered, black and yellow, FD&C dyes available from ERIS AND EVERALD such asFD&C Blue No. 2 and FD&C Red No. 40 and the like. Examples of thesuitable flavor include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry, grape flavor and a combination thereof.Examples of the suitable pH adjuster include citric acid, tartaric acid,phosphoric acid, hydrochloric acid and maleic acid. Examples of thesuitable sweetener include aspartame, acesulfame K and thaumatine.Examples of the suitable taste masking agent include sodium bicarbonate,ion exchange resins, cyclodextrin inclusion compounds, adsorbents andmicroencapsulated compounds.

Usually, the preparation contains the compound of the present inventionor a medicine to be used together in an amount of about 0.1 to about 50%by weight, preferably about 0.1 to about 30% by weight and, preferably,the preparation (the above sublingual tablet or buccal ant the like)allows 90% or more of the compound of the present invention or amedicine to be used together to be dissolved (in water) within a timeperiod of about 1 to about 60 minutes, preferably about 1 minute toabout 15 minutes, more preferably about 2 minutes to about 5 minutes, oris a oral quick disintegration preparation which disintegrates withinabout 1 to about 60 seconds, preferably about 1 to about 30 seconds,more preferably about 1 to about 10 seconds after being placed in theoral cavity.

The amount of the above excipient is about 10 to about 99% by weight,preferably about 30 to about 90% by weight based on the entirepreparation. The amount of β-cyclodextrin or β-cyclodextrin derivativeis about 0 to about 30% by weight based on the entire preparation. Theamount of the lubricant is about 0.01 to about 10% by weight, preferablyabout 1 to about 5% by weight based on the entire preparation. Theamount of the isotonicity is about 0.1 to about 90% by weight,preferably about 10 to about 70% by weight based on the entirepreparation. The amount of the hydrophilic carrier is about 0.1 to about50% by weight, preferably about 10 to about 30% by weight based on theentire preparation. The amount of the water-dispersible polymer is about0.1 to about 30% by weight, preferably about 10 to about 25% by weightbased on the entire preparation. The amount of the stabilizer is about0.1 to about 10% by weight, preferably about 1 to about 5% by weightbased on the entire preparation. If necessary, the preparation describedabove may further contain additives such as a colorant, a sweetener, apreservative and the like.

A daily dose of the combination preparations of the present invention isnot limited specifically and varies depending on the severity ofdisease, subject's age, sex, body weight and susceptibility, the periodand intervals of administration, the characteristics, formulation, typeand active components of the pharmaceutical preparation, and the like.The dose in terms of the compound of the present invention is notlimited specifically in so far as it causes no problematic side effects,but the daily oral dose in terms of the compound of the presentinvention per kg body weight in a mammal is about 0.005 to 100 mg,preferably about 0.05 to 50 mg, more preferably about 0.2 to about 30 mgand, usually, this is administered by dividing 1 to 3 times per day.

The compound of the present invention or a medicine to be used togethermay be employed in any amount within the range causing no problematicside effects. The daily dose of the compound of the present invention ora medicine to be used together is not limited specifically and variesdepending on the severity of disease, subject's age, sex, body weightand susceptibility, the period and intervals of administration, thecharacteristics, formulation, type and active components of thepharmaceutical preparation and the like. However, usually, the dailyoral dose per kg body weight in a mammal is about 0.001 to 2000 mg,preferably about 0.01 to 500 mg, more preferably about 0.1 to about 100mg in terms of the amount of the medicaments. Usually, this isadministered by dividing in 1 to 4 times per day.

When the combined preparations of the present invention areadministered, the compound of the present invention and a medicine to beused together may be administered at the same time. Alternatively, amedicine to be used together is first administered and then the compoundof the present invention is administered, or the compound of the presentinvention is first administered and then a medicine to be used togetheris administered. When they are administered at certain time intervals,the intervals vary depending on the active component to be administered,dosage form and administration method, and when a medicine to be usedtogether is first administered, the compound of the present inventionmay be administered within 1 minute to 3 days, preferably 10 minutes to1 day, more preferably 15 minutes to 1 hour after the administration ofthe medicine to be used together. When the compound of the presentinvention is first administered, a medicine to be used together may beadministered within 1 minute to 1 day, preferably 10 minutes to 6 hours,more preferably 15 minutes to 1 hour after the administration of thecompound of the present invention.

As a preferred administration method, for example, about 0.001 to 200mg/kg of a medicine to be used together in the form of an oral dosagepreparation is administered orally and, after about 15 minutes, about0.005 to 100 mg/kg of the compound of the present invention in the formof an oral dosage preparation is administered orally as a daily dose.

In the combination preparations of the present invention, the amount ofthe compound of the present invention based on the entire preparationvaries depending on the dosage form of the preparation, but is usually0.01 to 100% by weight, preferably 0.1 to 50% by weight, more preferably0.5 to 20% by weight based on the entire preparation.

EXAMPLES

The present invention will be further illustrated by the followingReference Examples, Examples, Preparation Examples and Experiments, butthey are not intended to restrict the present invention, and anymodification without departing from the scope of the present inventioncan be contemplated.

Elution in the column chromatography in the Reference Examples andExamples was carried out with observation by TLC (thin layerchromatography) unless otherwise specified. In the TLC observation,60F254 manufactured by Merck was used as a TLC plate and the samedevelopment solvent system as that used as the eluent in the columnchromatography was used. For detection, an UV detector was used. As thesilica gel for the column chromatography, Silica Gel 60 (70-230 mesh)manufactured by Merck was used. Usually, the term “room temperature”means a temperature of about 10° C. to 35° C. An extract was dried usingsodium sulfate or magnesium sulfate.

The abbreviations used in the Examples and Reference Examples mean asfollows.

-   NMR: nuclear magnetic resonance-   EI-MS: electron impact mass spectrometry-   SI-MS: secondary electron ion mass spectrometry-   DMF: dimethylformamide, THF: tetrahydrofuran, DMSO: dimethyl    dulfoxide, Hz: hertz, J: coupling constant, m: multiplet, q:    quartet, t: triplet, d: doublet, s: singlet, b: broad, like:    approximate

Example 1 3-Benzhydryl-1-methyl-4-piperidinone

To a solution of 11.3 g of 1-methyl-4-piperidinone (0.1 mole) in 50 mlof dichloromethane was added dropwise 20 ml of trimethylsilyltrifluoromethane sulfonate (hereinafter referred to as TMSOTf) underice-cooling. After stirring at room temperature for 25 minutes, 25 g ofbenzhydryl bromide and then 5 g of zinc bromide were added thereto.After stirring at room temperature for 16 hours, 100 ml of water and 20g of sodium acetate were added thereto and the mixture was stirredvigorously. The dichloromethane layer was separated and washed withwater. Then, 100 ml of ethanol and 8.4 ml of conc. hydrochloric acidwere added thereto, and the solvent was distilled off under reducedpressure. The residue (crystal) was triturated with ethanol and filteredto obtain 20.6 g of the hydrochloride of the title compound (yield:53%).

mp 252-253° C.

IR (KBr) 3025, 2950, 2900, 2475, 1730, 1490, 1450, 1090, 745, 700, 695,540 cm⁻¹.

To a mixture of an ice cooled aqueous solution of sodium hydroxide (4 gof sodium hydroxide and 200 ml of water) and 200 ml of dichloromethanewas added 29.3 g of the hydrochloride of the title compound, and themixture was stirred vigorously. The dichloromethane layer was separatedand dried over anhydrous magnesium sulfate. Then, the solvent wasdistilled off under reduced pressure. The residue (crystal) wastriturated with hexane and filtered. After drying, 24 g of the titlecompound was obtained.

mp 127-128° C.

IR (KBr) 3025, 2970, 2950, 2940, 2800, 1710, 1595, 1490, 1450, 1375,1145, 1060, 745, 705, 695, 545 cm⁻¹.

Example 2 4-Benzhydryl-1-ethyl-3-piperidinone

To 100 ml of dichloromethane were added 8 g of 1-ethyl-3-piperidinonehydrochloride and 20 ml of water, and 5 g of sodium carbonate was addedthereto with stirring vigorously under ice-cooling. The dichloromethanelayer was separated and dried over anhydrous magnesium sulfate. Then,the solvent was distilled off under reduced pressure to obtain 5 g ofthe free form of 1-ethyl-3-piperidinone as a residue. To a solution of1.4 g of the free form obtained in 5 ml of dichloromethane were added 4ml of TMSOTf and 1.8 g of benzhydrol with stirring under ice-cooling.After stirring at room temperature for 16 hours, ice-water was addedthereto and the mixture was neutralized with sodium bicarbonate. Afterthe dichloromethane layer was dried over anhydrous magnesium sulfate,the solvent was distilled off under reduced pressure. The residue waspurified by subjecting it to silica gel column chromatography (100 g,ethyl acetate). The solvent was distilled off, and the residue (crystal)was triturated with a small amount of ethyl ether and filtered to obtain0.68 g of the title compound (yield: 70%).

mp 73-74° C.

IR (KBr) 3025, 2960, 2925, 2800, 1725, 1490, 1450, 1090, 750, 710, 695,560 cm⁻¹.

Example 3 4-Benzhydryl-1-benzyl-3-piperidinone

To 150 ml of dichloromethane were added 10 g of 1-benzyl-3-piperidinonehydrochloride and 50 ml of water, and 6 g of sodium carbonate was addedto the mixture with stirring vigorously under ice-cooling. After thedichloromethane layer was dried over anhydrous magnesium sulfate, thesolvent was distilled off under reduced pressure. The residue wasdissolved in 50 ml of dichloromethane, 18 ml of TMSOTf and 8.2 g ofbenzhydrol were added thereto with stirring under ice-cooling. Afterstirring at room temperature for 16 hours, 100 ml of ice-water and 20 gof sodium acetate were added thereto and the mixture was stirredvigorously. After the dichloromethane layer was washed with water, 50 mlof ethanol and 5 ml of conc. hydrochloric acid were added thereto, andthe solvent was distilled under reduced pressure. The residue (crystal)was triturated with ethanol and filtered to obtain 12.4 g of thehydrochloride of the title compound (yield: 72%).

mp 170-171° C.

To a calculated amount of 1 N aqueous solution of sodium hydroxide andthe same volume of dichloromethane was added the above hydrochloride andthe mixture was stirred vigorously. The dichloromethane layer wasseparated and dried over magnesium sulfate, and then the solvent wasdistilled off under reduced pressure to obtain the title compound.

mp 106-107° C.

IR (KBr) 3025, 2950, 1710, 1595, 1490, 1450, 1360, 740, 700, 550 cm⁻¹.

Example 4 3-Benzhydryl-1-benzyl-4-piperidinone

To a solution of 95 g of 1-benzyl-4-piperidinone in 250 ml ofdichloromethane was added dropwise 100 ml of TMSOTf with stirring underice-cooling. After stirring at room temperature for 25 minutes, 125 g ofbenzhydryl bromide and then 5 g of zinc bromide were added thereto.After stirring at room temperature for 16 hours, 100 ml of water and 100g of sodium acetate were added and the mixture was stirred vigorously.The dichloromethane layer was separated and washed with water. Then, 200ml of ethanol and 100 ml of conc. hydrochloric acid were added theretoand the solvent was distilled off under reduced pressure. The residue(crystal) was triturated with ethanol to obtain 144 g of thehydrochloride of the title compound (74%).

mp 202-207° C.

IR (KBr) 3250, 2900, 2450, 2360, 1730, 1490, 1450, 760, 745, 705, 595,540, 520 cm⁻¹.

The above hydrochloride was treated with an aqueous solution of sodiumbicarbonate to obtain the title compound.

¹H-NMR (CDCl₃) δ: 2.20-2.40, 2.50-2.70, 2.75-2.90 (each m, 6H),3.30-3.40 (m, 1H), 3.44 and 3.54 (ABq, 2H, J=13.2 Hz), 4.64 (d, 1H,J=11.2 Hz), 7.17, 7.27 (each m, 15H).

Example 5 1-Acetyl-3-benzhydryl-4-piperidinone

To a solution of 77 g of 1-acetyl-4-piperidinone in 300 ml ofdichloromethane was added 200 ml of TMSOTf with stirring underice-cooling. Then, 92 g of benzhydrol was added thereto. After allowingto stand the mixture at room temperature overnight, 500 ml of water and50 g of sodium acetate were added thereto and the mixture was stirredvigorously. The dichloromethane layer was separated, washed with anaqueous solution of sodium bicarbonate, and then dried over magnesiumsulfate. The solvent was distilled off under reduced pressure. To theresidue was added 100 ml of ethyl ether, and a precipitate was collectedby filtration to obtain 132.6 g of the title compound (yield: 86%).

mp 133-136° C.

IR (KBr) 3060, 3025, 2900, 2860, 1715, 1640, 1490, 1450, 1420, 1250,980, 745, 705, 695 cm⁻¹.

Example 6 1-Acetyl-3-[bis(4-chlorophenyl)methyl]-4-piperidinone

According to the same manner as that described in Example 5, the titlecompound was obtained (yield: 94%).

mp 169-171° C.

IR (KBr) 2860, 1720, 1640, 1490, 1455, 1440, 1425, 1300, 1090, 1015,895, 810, 795, 540, 500 cm⁻¹.

Example 7 1-Acetyl-3-[bis(4-fluorophenyl)methyl]-4-piperidinone

According to the same manner as that described in Example 5, the titlecompound was obtained (yield: 86%).

mp 146-147° C.

IR (KBr) 2850, 1715, 1640, 1600, 1505, 1440, 1420, 1300, 1220, 1160,1010, 820, 765, 605, 575, 545, 525 cm⁻¹.

Example 81-Acetyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-4-piperidinone

According to the same manner as that described in Example 5, the titlecompound was obtained (yield: 15%).

mp 107-109° C.

IR (KBr) 2900, 1710, 1665, 1630, 1430, 1310, 1230, 1020, 770 cm⁻¹.

Example 9 1-Acetyl-3-(9H-xanthen-9-yl)-4-piperidinone

To a solution of 8 g of 1-acetyl-4-piperidinone in 50 ml ofdichloromethane was added dropwise 20 ml of TMSOTf with stirring underice-cooling. After cooling to −78° C, 10 g of xanthohydrol was addedthereto, and then the mixture was stirred for 2 hours (bat temperaturewas raised from −78° C. to −50° C.). After raising to 0° C., the mixturewas stirred for additional 2 hours. After the reaction mixture waswashed with water, the solvent was distilled off under reduced pressure.The residue (crystal) was triturated with ethyl ether and filtered.After drying, 9.5 g of the title compound (yield: 52%) was obtained.

mp 175-176° C.

IR (KBr) 1715, 1620, 1680, 1445, 1420, 1250, 760 cm¹.

Example 10 3-Benzhydryl-1-ethyl-4-piperidinone

To a solution of 25.4 g of 1-ethyl-4-piperidinone (0.2 mole) in 100 mlof dichloromethane was added dropwise 40 ml of TMSOTf over 20 minuteswith stirring under ice-cooling. After stirring at room temperature for25 minutes, 25 g of benzhydryl bromide and then 5 g of zinc bromide wereadded thereto. After stirring at room temperature for 16 hours, 100 mlof water and 20 g of sodium acetate were added and the mixture wasstirred vigorously. The dichloromethane layer was separated and washedwith water, and then the solvent was distilled off. The residue waspurified by subjecting it to silica gel column chromatography (300 g,ethyl acetate:hexane=1:1). The solvent was distilled off, and theresidue (crystal) was triturated with hexane and filtered to obtain 33 gof the title compound (yield: 56%).

mp 54-58° C.

IR (KBr) 2970, 2790, 1715, 1495, 1445, 1230, 1145, 740, 700 cm⁻¹.

Example 11 3-Benzhydryl-1-propyl-4-piperidinone

According to the same manner as that described in Example 10, the titlecompound was obtained (yield: 42%).

mp 72-76° C.

IR (KBr) 2960, 2800, 1715, 1495, 1450, 1370, 1230, 1120, 740, 700 cm⁻¹.

Example 12 3-Benzhydryl-1-(2-phenylethyl)-4-piperidinone

According to the same manner as that described in Example 10, the titlecompound was obtained (yield: 38%).

mp 73-76° C.

IR (KBr) 2960, 2780, 1715, 1450, 1225, 1130, 740, 700 cm⁻¹.

Reference Example 1 1-(2-Methoxybenzyl)-4-piperidinone

To a solution of 14.3 g of 4-piperidinone, 13.8 g of 2-methoxybenzylalcohol and 35 ml of diisopropylethylamine in 50 ml of dichloromethanewas added 24 ml of ethyl o-phenylene phosphate (EPPA) with stirringunder ice-cooling. After allowing to stand at room temperature for 4days, the reaction mixture was washed with water, and the solvent wasdistilled off under reduced pressure. To the residue were added 300 mlof water, 100 ml of acetone and 25 ml of conc. hydrochloric acid and themixture was stirred in an oil bath at 70° C. for 16 hours. Acetone wasdistilled off under reduced pressure, and the mixture was neutralizedwith sodium bicarbonate. The mixture was extracted with dichloromethane,the extract was dried over magnesium sulfate, and the solvent wasdistilled off under reduced pressure. To the residue were added 100 mlof acetone and 10 ml of conc. hydrochloric acid, and the solvent wasdistilled off under reduced pressure. The residue was dissolved inacetone and cooled in ice. Precipitated crystals were collected byfiltration to obtain 17.6 g of the hydrochloride of the title compound.

mp 173-175° C.

IR (KBr) 3330, 3280, 2940, 2700, 2650, 2560, 1600, 1495, 1470, 1440,1290, 1255, 1150, 1100, 1040, 985, 960, 760, 600 cm⁻¹.

A solution of 17.6 g of the hydrochloride of the title compound, 10 g ofsodium bicarbonate, 30 ml of water and 100 ml of dichloromethane wasstirred vigorously. The dichloromethane layer was separated and driedover magnesium sulfate, and then the solvent was distilled off underreduced pressure to obtain 13.7 g of the title compound (yield: 62.8%).

¹H-NMR (CDCl₃) δ: 2.50 (t, 4H, J=6 Hz), 2.82 (t, 4H, J=6 Hz), 3.70 (s,2H), 3.83 (s, 3H), 6.85-7.41 (m, 4H).

Example 13 1-(2-Methoxybenzyl)-3-(9H-xanthen-9-yl)-4-piperidinone

To a solution of 2.2 g of 1-(2-methoxybenzyl)-4-piperidinone in 20 ml ofdichloromethane were added 4 ml of TMSOTf and then 1.9 g of xanthohydrolwith stirring under ice-cooling. After stirring for 1 hour underice-cooling, 30 ml of water was added and the mixture was neutralizedwith sodium bicarbonate. After the reaction mixture was washed withwater, and the solvent was distilled off under reduced pressure. To theresidue was added ethyl acetate and the mixture was filtered. Thefiltrate was concentrated, and purified by subjecting it to silica gelcolumn chromatography (100 g, ethyl acetate:hexane=1:4). The desiredfraction was concentrated, and precipitated crystals were collected byfiltration to obtain 0.89 g of the title compound (yield: 22%).

mp 96-97° C.

IR (KBr) 2800, 1720, 1600, 1480, 1460, 1240, 1100, 1025, 765 cm⁻¹.

Example 143-(5H-Dibenzo[a,d]cyclohepten-5-yl)-1-(2-methoxybenzyl)-4-piperidinone

To a solution of 2.2 g of 1-(2-methoxybenzyl)-4-piperidinone in 20 ml ofdichloromethane was added 4 ml of TMSOTf with stirring underice-cooling. After 5 minutes, 2 g of dibenzosuberenol was added withstirring at −50° C. The mixture was stirred for 60 minutes as it was(bath temperature was raised from −50° C. to −10° C. during this time).To the mixture was added 20 ml of water and the resulting mixture wasneutralized with sodium bicarbonate. The dichloromethane layer wasseparated, washed with an aqueous solution of sodium bicarbonate, andthen dried over magnesium sulfate. The solvent was distilled off underreduced pressure. To the residue was added a small amount of ethyl etherand precipitated crystals were collected by filtration to obtain 1.78 gof the title compound (yield: 44%).

mp 113-114° C.

IR (KBr) 2775, 1710, 1600, 1590, 1495, 1440, 1255, 1195, 1120, 1035,810, 780, 760, 560, 460 cm⁻¹.

Example 15 3-[Bis(4-methoxyphenyl)methyl]-1-methyl-4-piperidinone

To a solution of 1.13 g of 1-methyl-4-piperidinone in 10 ml ofdichloromethane was added 4 ml of TMSOTf. Then, 2.44 g of4,4′-dimethoxybenzhydrol was added thereto slowly. After allowing tostand at −50° C. for 45 minutes, ice-water was added thereto and themixture was stirred vigorously. After addition of 20 ml of ethylacetate, the mixture was basified with sodium bicarbonate. The ethylacetate layer was dried over magnesium sulfate and purified bysubjecting it to silica gel column chromatography (40 g, ethyl acetate).The solvent was distilled off under reduced pressure, hexane was addedto the residue, and the resulting crystals were collected by filtrationto obtain 1.12 g of the title compound (yield: 33%).

mp 104.5-106° C.

IR (KBr) 2950, 2840, 2810, 1715, 1610, 1515, 1470, 1305, 1260, 1250,1180, 1030, 850, 830, 810, 560, 550 cm⁻¹.

Example 16 3-[Bis(4-chlorophenyl)methyl]-1-methyl-4-piperidinone

To a solution of 1.13 g of 1-methyl-4-piperidinone in 15 ml ofdichloromethane were added 4 ml of TMSOTf and then 2.5 g of4,4′-dichlorobenzhydrol under ice-cooling. After stirring at roomtemperature overnight, 20 ml of water was added thereto and the mixturewas neutralized with sodium bicarbonate. The dichloromethane layer wasconcentrated under reduced pressure, and then purified by subjecting itto silica gel column chromatography (40 g, ethyl acetate). The solventwas distilled off under reduced pressure, hexane was added to theresidue, and the resulting crystals were collected by filtration toobtain 2.26 g of the title compound (yield: 65%).

mp 146-147° C.

IR (KBr) 2975, 2780, 1715, 1490, 1415, 1140, 1090, 1015, 820, 795, 550,500 cm⁻¹.

Example 17 1-Methyl-3-(9H-xanthen-9-yl)-4-piperidinone

To a solution of 1.13 g of 1-methyl-4-piperidinone in 15 ml ofdichloromethane were added 4 ml of TMSOTf and then 1.98 g ofxanthohydrol under ice-cooling. The mixture was stirred underice-cooling for 60 minutes and 20 ml of water was added thereto. Themixture was neutralized with sodium bicarbonate. The dichloromethanelayer was separated, and the solvent was distilled off under reducedpressure. The residue was purified by subjecting it to silica gel columnchromatography (40 g, chloroform:methanol=13:5). The solvent wasdistilled off, and crystals were triturated with ethyl ether andfiltered. After drying, 0.89 g of the title compound (yield: 30%) wasobtained.

mp 160-162° C.

IR (KBr) 2950, 2800, 1710, 1480, 1460, 1250, 770, 760 cm⁻¹.

Example 18 1-Benzyl-3-(9H-xanthen-9-yl)-4-piperidinone

To a solution of 1.13 g of 1-benzyl-4-piperidinone in 15 ml ofdichloromethane were added 4 ml of TMSOTf and then 1.98 g ofxanthohydrol under ice-cooling. The mixture was stirred underice-cooling for 60 minutes and 20 ml of water added thereto. The mixturewas neutralized with sodium bicarbonate. The dichloromethane layer wasseparated and the solvent was distilled off under reduced pressure. Theresidue was purified by subjecting it to silica gel columnchromatography (100 g, ethyl acetate:hexane=1:1). The solvent wasdistilled off, and the resulting crystals were triturated with hexaneand filtered. After drying, 0.76 g of the title compound (yield: 21%)was obtained.

mp 124-125° C.

IR (KBr) 2960, 2760, 1710, 1475, 1460, 1255, 1190, 1095, 900, 765, 755,695, 510, 480 cm⁻¹.

Example 19 1-Methyl-3-(9H-thioxanthen-9-yl)-4-piperidinone

To a solution of 1.13 g of 1-methyl-4-piperidinone in 15 ml ofdichloromethane was added 4 ml of TMSOTf under ice-cooling. The mixturewas cooled to −78° C. and 1.98 g of thioxanthohydrol was added thereto.The mixture was stirred at the same temperature for 60 minutes. To thereaction mixture was added 20 ml of water and the mixture wasneutralized with sodium bicarbonate. The dichloromethane layer wasseparated, and the solvent was distilled off under reduced pressure. Theresidue was purified by subjecting it to silica gel columnchromatography (40 g, chloroform:methanol=13:5). The solvent wasdistilled off, and the resulting crystals were triturated with ethylether and filtered. After drying, 0.56 g of the title compound (yield:18%) was obtained.

mp 155-156° C.

IR (KBr) 2940, 2800, 1710, 1470, 1440, 1375, 1240, 1135, 1060, 780, 750,575, 490 cm⁻¹.

Example 20

3-[Bis(4-fluorophenyl)methyl]-1-methyl-4-piperidinone

To a solution of 2.2 g of 1-methyl-4-piperidinone in 40 ml ofdichloromethane was added dropwise 8 ml of TMSOTf under ice-cooling.After stirring at room temperature for 25 minutes, 3.7 g of4,4′-difluorobenzhydrol was added thereto. After stirring at roomtemperature for 16 hours, 50 ml of water was added and the mixture wasneutralized with sodium bicarbonate. The dichloromethane layer wasseparated, washed with water, and then dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure, and theresidue (crystal) was triturated with hexane and filtered to obtain 4.7g of the title compound (yield: 88%).

mp 127-129° C.

IR (KBr) 2970, 2940, 2800, 2780, 1715, 1600, 1510, 1505, 1230, 825, 560,540 cm⁻¹.

Example 21 1-Benzyl-3-[bis(4-fluorophenyl)methyl]-4-piperidinone

To a solution of 10 g of 1-benzyl-4-piperidinone in 50 ml ofdichloromethane was added dropwise 20 ml of TMSOTf with stirring underice-cooling. After stirring at room temperature for 15 minutes, 11 g of4,4′-difluorobenzhydrol was added thereto. After stirring at roomtemperature for 16 hours, 50 ml of water was added thereto and themixture was neutralized with sodium acetate. The dichloromethane layerwas separated and washed with water, and then the solvent was distilledoff under reduced pressure to obtain the title compound as an oil.

¹H-NMR (CDCl₃) δ: 2.30-2.75, 2.80-2.94 (each m, 6H), 3.20-3.30 (m, 1H),3.42 and 3.57 (ABq, 2H, J=13 Hz), 4.61 (d, 1H, J=11 Hz), 6.81-7.30 (m,13H).

To the above oil were added 50 ml of ethanol and 10 ml of conc.hydrochloric acid, and the solvent was distilled off under reducedpressure. The residue (crystal) was triturated with hexane and filteredto obtain 16.9 g of the hydrochloride of the title compound (yield:79%).

mp 180-182° C.

IR (KBr) 2900, 2450, 2390, 1735, 1600, 1510,. 1455, 1405, 1415, 1240,1230, 1220, 1160, 825, 770, 700, 580, 550, 530, 520 cm⁻¹.

Example 22 1-Benzyl-3-[bis(4-chlorophenyl)methyl]-4-piperidinone

To a solution of 1.9 g of 1-benzyl-4-piperidinone in 20 ml ofdichloromethane were added 4 ml of TMSOTf and 2.5 g of4,4′-dichlorobenzhydrol with stirring under ice-cooling. After stirringat room temperature for 18 hours, 50 ml of water was added thereto andthe mixture was neutralized with sodium bicarbonate. The dichloromethanelayer was washed with water, and the solvent was distilled off underreduced pressure. The residue was purified by subjecting it to silicagel column chromatography (100 g, ethyl acetate:hexane=1:1) to obtainthe title compound as an oil.

¹H-NMR (CDCl₃) δ: 2.30-2.90 (each m, 6H), 3.20-3.34(m, 1H), 3.42 and3.57 (ABq, 2H, J=12.9 Hz), 4.56 (d, 1H, J=11 Hz), 7.00-7.32 (m, 13H).

To the above oil were added 30 ml of ethanol and 0.84 ml of conc.hydrochloric acid and the solvent was distilled off under reducedpressure. The residue (crystal) was triturated with ethanol and filteredto obtain 3.3 g of the hydrochloride of the title compound (yield: 72%).

mp 192-195° C.

IR (KBr) 2900, 2450, 2380, 1730, 1490, 1090, 1010, 795, 700, 525 cm⁻¹.

Example 23 3-[(4-Chlorophenyl)(phenyl)methyl]-1-methyl-4-piperidinone

To a solution of 2.3 g of 1-methyl-4-piperidinone in 40 ml ofdichloromethane were added 8 ml of TMSOTf and 4.2 g of4-chlorobenzhydrol with stirring under ice-cooling. After stirring atroom temperature for 16 hours, 50 ml of water was added thereto and themixture was neutralized with sodium bicarbonate. The dichloromethanelayer was washed with water, and then dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure to obtain the titlecompound as an oil.

¹H-NMR (CDCl₃) δ: 2.27, 2.28 (each s, 3H), 2.27-2.40, 2.40-2.85 (each m,6H), 3.41 (m, 1H), 4.50 (d, 1/2H, J=11.6 Hz), 4.55 (d, 1/2H, J=11.2 Hz),7.10-7.35 (m, 9H).

To the above oil were added 20 ml of ethanol and 1.6 ml of conc.hydrochloric acid and the solvent was distilled off under reducedpressure. The residue (crystal) was triturated with ethanol and filteredto obtain 3.3 g of the hydrochloride of the title compound (yield: 47%).

mp 192-193° C.

IR (KBr) 2950, 2460, 1730, 1490, 1090, 1015, 755, 700, 545 cm⁻¹.

Example 24 1-Benzyl-3-[(4-chlorophenyl)(phenyl)methyl]-4-piperidinone

To a solution of 1.9 g of 1-benzyl-4-piperidinone in 20 ml ofdichloromethane were added 4 ml of TMSOTf and 2.1 g of4-chlorobenzhydrol with stirring under ice-cooling. After stirring atroom temperature for 16 hours, 50 ml of water was added thereto and themixture was neutralized with sodium bicarbonate. The dichloromethanelayer was washed with water, and then dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure to obtain the titlecompound as an oil.

¹H-NMR (CDCl₃) δ: 2.30-2.90 (m, 6H), 3.25-3.40 (m, 1H), 3.39-3.62 (m,2H), 4.59 (d, 1/2H, J=11.4 Hz), 4.62 (d, 1/2H, J=11.2 Hz), 7.05-7.40 (m,14H).

To the above oil were added 20 ml of ethanol and 2 ml of conc.hydrochloric acid and the solvent was distilled off under reducedpressure. The residue (crystal) was triturated with ethanol and filteredto obtain 2.9 g of the hydrochloride of the title compound (yield: 74%).

mp 175-178° C.

IR (KBr) 2900, 2450, 2380, 1730, 1490, 1450, 1090, 1015, 760, 700, 545,525 cm⁻¹.

Example 253-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1-methyl-4-piperidinone

To a solution of 1.13 g of 1-methyl-4-piperidinone in 20 ml ofdichloromethane was added 4 ml of TMSOTf with stirring underice-cooling. After addition of 2.1 g of dibenzosuberol cooled to −50°C., the mixture was stirred at the same temperature for 2 hours and 20ml of water was added thereto. The mixture was neutralized with sodiumbicarbonate. The dichloromethane layer was separated, washed with water,and dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure, and the residue (crystal) was trituratedwith hexane and filtered to obtain 1.4 g of the title compound (yield:46%).

mp 146-147° C.

IR (KBr) 2940, 2790, 1715, 1230, 1135, 780, 755, 740, 560 cm⁻¹.

Example 26 3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-1-methyl-4-piperidinone

To a solution of 1.13 g of 1-methyl-4-piperidinone in 15 ml ofdichloromethane was added 4 ml of TMSOTf with stirring underice-cooling. After addition of 2.1 g of dibenzosuberenol cooled to −70°C., the mixture was stirred at the same temperature for 1 hour and 20 mlof water was added thereto. The mixture was neutralized with sodiumbicarbonate. The dichloromethane layer was separated, washed with water,and dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure, and the residue was subjected to silica gelcolumn chromatography eluting with ethyl acetate. After distilling offthe solvent, the residue (crystal) was triturated with hexane andfiltered to obtain 1 g of the title compound (yield: 33%).

mp 144-158° C.

IR (KBr) 2960, 2775, 1710, 1480, 1360, 1270, 1250, 1220, 115.5, 1135,1050, 795, 780, 760, 725, 550, 465 cm⁻¹.

Example 27

1-Benzyl-3-(5H-dibenzo[a,d]cyclohepten-5-yl)-4-piperidinone

To a solution of 10 g of 1-benzyl-4-piperidinone in 100 ml ofdichloromethane was added 4 ml of TMSOTf with stirring underice-cooling. After addition of 10 g of dibenzosuberenol cooled to −50°C., the mixture was stirred for 1 hour (bath temperature was raised from−50° C. to 0° C.) Then, 20 ml of water was added and the mixture wasneutralized with sodium bicarbonate. The dichloromethane layer wasseparated, washed with water, and then dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure, and theresidue (crystal) was triturated with ethyl acetate and filtered toobtain 12.7 g of the title compound (yield: 67%).

mp 167-169° C.

IR (KBr) 2825, 1705, 1495, 1340, 1240, 1185, 1115, 810, 780, 730, 700,465 cm⁻¹.

Example 28 3-Benzhydryl-4-piperadinone

To 10.2 g of 1-acetyl-3-benzhydryl-4-piperidinone were added 200 ml ofwater and 200 ml of conc. hydrochloric acid and the mixture was heatedfor 5 hours. Further, after stirring at 80° C. overnight, the mixturewas filtered while hot, and the filtrate was concentrated under reducedpressure. The residue (crystal) was triturated with ethanol and filteredto obtain 8 g of the hydrochloride of the title compound (yield: 80%).

mp 208-210° C.

IR (KBr) 2980, 2800, 2710, 1735, 1590, 1450, 1385, 1170, 755, 710, 700,540 cm⁻¹.

Example 29 3-[Bis(4-chlorophenyl)methyl]-4-piperidinone

According to the same manner as that described in Example 28, thehydrochloride of the title compound was obtained (yield: 77%).

mp 145-147° C.

IR (KBr) 3400, 2900, 2700, 1730, 1590, 1490, 1410, 1090, 1010, 810, 790,540, 500 cm⁻¹.

Example 30 3-[Bis(4-fluorophenyl)methyl]-4-piperidinone

According to the same manner as that described in Example 28, thehydrochloride of the title compound was obtained (yield: 97%).

mp 122-123° C.

IR (KBr) 3420, 2920, 2700, 2490, 1730, 1600, 1505, 1220, 1155, 825, 570,550, 525 cm⁻¹.

Example 31 4-Benzhydryl-3-piperidinone

To a solution of 12 g of 4-benzhydryl-1-benzyl-3-piperidinonehydrochloride in 250 ml of methanol was added 6 g of 10% Pd—C hydratedpowder (Nippon Engelhard Ltd.), and the mixture was stirred in a streamof hydrogen. After a calculated amount of the hydrogen was absorbed, themixture was filtered and the filtrate was concentrated under reducedpressure. The residue (crystal) was triturated with ethanol and filteredto obtain 7 g of the hydrochloride of the title compound (yield: 76%).

mp 203-207° C.

IR (KBr) 3425, 2925, 2700, 2450, 1730, 1600, 1490, 1450, 1420, 1375,1305, 1235, 1155, 1070, 1030, 770, 745, 705, 690, 535 cm⁻¹.

Example 32 3-Benzhydryl-1-(2-methoxybenzyl)-4-piperidinone

To a solution of 1 g of 3-benzhydryl-4-piperidinone hydrochloride, 0.5 gof 2-methoxybenzyl alcohol and 1.7 g of diisopropylethylamine in 10 mlof dichloromethane was added 1 ml of EPPA. After allowing to stand atroom temperature for 16 hours, the solvent was distilled off underreduced pressure. The residue was purified by subjected it to silica gelcolumn chromatography (100 g, ethyl acetate). Recrystallization from 3ml of ethyl ether gave 0.87 g of the title compound (yield: 68%).

mp 114-116° C.

IR (KBr) 3010, 2900, 2780, 1705, 1590, 1575, 1490, 1455, 1430, 1315;1280, 1235, 1170, 1110, 1080, 1015, 750, 695, 540 cm⁻¹.

Example 33 4-Benzhydryl-1-(2-methoxybenzyl)-3-piperidinone

To a solution of 1 g of 4-benzhydryl-3-piperidinone hydrochloride, 0.5 gof 2-methoxybenzyl alcohol and 1.7 g of diisopropylethylamine in 10 mlof dichloromethane was added 1 ml of EPPA. After allowing to stand atroom temperature for 16 hours, the solvent was distilled off underreduced pressure. The residue was purified by subjecting it to silicagel column chromatography (100 g, ethyl acetate:hexane=1:1). The oilytitle compound was dissolved in 5 ml of ethanol and 0.3 ml of conc.hydrochloric acid. Crystals precipitated were collected by filtration toobtain 0.5 g of the hydrochloride of the title compound (yield: 36%).

mp 195-196° C.

IR (KBr) 2925, 2460, 2360, 1730, 1605, 1495, 1425, 1255, 1030, 970, 750,710, 540 cm⁻¹.

Example 34 3-Benzhydryl-1-[1-(2-methoxyphenyl)ethyl]-4-piperidinone

To a solution of 3 g of 3-benzhydryl-4-piperidinone hydrochloride, 1.5 gof (±)-1-(2-methoxyphenyl)ethanol and 5.1 g of diisopropylethylamine is30 ml of dichloromethane was added 3 ml of EPPA. After allowing to standat room temperature for 16 hours, the solvent was distilled off underreduced pressure. The residue was purified by subjecting it to silicagel column chromatography (100 g, ethyl acetate:hexane=1:1) to obtainthe title compound as an oil.

¹H-NMR (CDCl₃) δ: 1.51 (d, 3H, J=6.5 Hz), 2.20-2.90 (m, 7H), 3.40 (m,1H), 3.70, 3.76 (each s, 3H), 4.54, 4.63 (each d, 1H, J=11 Hz),6.79-7.45 (m, 14H).

The above oil was dissolved in 5 ml of ethanol and 0.8 ml of conc.hydrochloric acid, and the solvent was distilled off under reducedpressure. After washing with ethyl ether, the residue was decanted anddried to obtain 1.18 g of the hydrochloride of the title compound(yield: 27%).

mp 125-127° C.

IR (KBr) 3425, 2975, 2350, 1730, 1600, 1495, 1450, 1250, 1020, 745, 705,540 cm⁻¹.

Example 353-[Bis(4-chlorophenyl)methyl]-1-(2-methoxybenzyl)-4-piperidinone

According to the same manner as that described in Example 33, thehydrochloride of the title compound was synthesized (yield: 70%).

mp 186-187° C.

IR (KBr) 2940, 2500, 2400, 1720, 1605, 1495, 1470, 1410, 1260, 1090,1015, 815, 755 cm⁻¹.

Example 363-[Bis(4-fluorophenyl)methyl]-1-(2-methoxybenzyl)-4-piperidinone

According to the same manner as that described in Example 33, thehydrochloride of the title compound was synthesized (yield: 51%).

mp 164-166° C.

IR (KBr) 2950, 2475, 2400, 1725, 1605, 1510, 1470, 1255, 1230, 1220,1160, 1030, 840, 825, 755, 555, 530 cm⁻¹.

Example 37 3-Benzhydryl-1-[bis(4-methoxyphenyl)methyl]-4-piperidinone

To a solution of 1 g of 3-benzhydryl-4-piperidinone hydrochloride, 0.8 gof 4,4′-dimethoxybenzhydrol and 1.7 ml of diisopropylethylamine in 10 mlof dichloromethane was added 1 ml of EPPA. After allowing to stand atroom temperature for 3 hours, the reaction mixture was washed withwater, and the solvent was distilled off under reduced pressure.Recrystallization from ethyl ether gave 1.3 g of the title compound(yield: 79%).

mp 137-139° C.

IR (KBr) 2960, 2800, 1720, 1605, 1510, 1465, 1300, 1250, 1170, 1085,1035, 815, 700, 560, 540 cm⁻¹.

Example 38 3-Benzhydryl-1-(2-hydroxybenzyl)-4-piperidinone

To a solution of 1 g of 3-benzhydryl-4-piperidinone hydrochloride, 0.5 gof 2-hydroxybenzyl alcohol and 1.7 ml of diisopropylethylamine in 15 mlof dichloromethane was added 1 ml of EPPA. After stirring at roomtemperature for 1 hour, the reaction mixture was washed with water, andthe solvent was distilled off under reduced pressure. The residue waspurified by subjecting it to silica gel column chromatography (100 g,ethyl acetate). Recrystallization from ethyl ether gave 0.78 g of thetitle compound (yield: 63%).

mp 109-110° C.

IR (KBr) 2840, 1730, 1590, 1495, 1470, 1450, 1415, 1365, 1260, 1235,1090, 760, 700, 545 cm⁻¹.

Example 39 3-Benzhydryl-1-(3-hydroxybenzyl)-4-piperidinone

According to the same manner as that described in Example 38, the titlecompound was obtained (yield: 75%).

mp 134-137° C.

IR (KBr) 3250, 3010, 2800, 1685, 1670, 1585, 1490, 1475, 1440, 1350,1330, 1270, 1250, 750, 700, 685, 535 cm⁻¹.

Example 40 3-Benzhydryl-1-(4-hydroxybenzyl)-4-piperidinone

According to the same manner as that described in Example 38, the titlecompound was obtained (yield: 66%).

mp 133-134° C.

IR (KBr) 2800, 1720, 1615, 1595, 1515, 1495, 1450, 1240, 750, 700 cm⁻¹.

To an ethanol solution of the title compound was added a calculatedamount of conc. hydrochloric acid and the solvent was distilled offunder reduced pressure. Ethyl ether was added to the residue, and theresulting crystalline powder was collected by filtration to obtain thehydrochloride of the title compound.

mp 149-150° C.

IR (KBr) 2930, 1735, 1610, 1585, 1510, 1465, 1450, 1300, 121, 1030, 705cm⁻¹.

Example 41 3-Benzhydryl-1-(4-hydroxy-3-methoxybenzyl)-4-piperidinone

According to the same manner as that described in Example 38, the titlecompound was obtained (yield: quantitative).

mp 131-132° C.

IR (KBr) 3010, 2950, 2800, 1715, 1600, 1515, 1485, 1460, 1445, 1340,1270, 1230, 1150, 1025, 740, 700 cm⁻¹.

Example 42 3-Benzhydryl-1-(1,3-benzodioxol-5-ylmethyl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was obtained (yield: 38%).

mp 113-114° C.

IR (KBr) 3010, 2860, 2780, 1705, 1590, 1495, 1480, 1430, 1240, 1175,1025, 920, 730 cm⁻¹.

Example 43 3-Benzhydryl-1-(2,3-dimethoxybenzyl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was obtained as an oil (yield: 54%).

¹H-NMR (CDCl₃) δ: 2.25-2.90(m, 6H), 3.35 (m, 1H), 3.50 and 3.59 (ABq,2H, J=13 Hz), 3.81, 3.87 (each s, 6H), 4.64 (d, 1H, J=11 Hz), 6.80-7.32(m, 13H).

To the above oil were added ethanol and a calculated amount of conc.hydrochloric acid, and the solvent was distilled off under reducedpressure. Ethyl ether was added to the residue, and the resultingcrystalline powder was collected by filtration to obtain thehydrochloride of the title compound.

mp 157-160° C.

IR (KBr) 2900, 2450, 2360, 1730, 1580, 1480, 1445, 1425, 1270, 1075,1000, 740, 695, 535 cm⁻¹.

Example 44 3-Benzhydryl-1-(2, 4-dimethoxybenzyl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was obtained as an oil.

¹H-NMR (CDCl₃) δ: 2.35-3.00 (m, 6H), 3.40 (m, 1H), 3.54 (s, 2H), 3.78,3.86 (each s, 6H), 4.64 (d, 1H, J=11 Hz), 6.47, 7.10-7.40 (m, 13H).

To the above oil were added ethanol and a calculated amount of conc.hydrochloric acid, and the solvent was distilled off under reducedpressure. Ethyl ether was added to the residue, and the resultingcrystalline powder was collected by filtration to obtain 1.6 g of thehydrochloride of the title compound (yield: 71%).

mp 173-174° C.

IR (KBr) 2930, 1735, 1610, 1585, 1510, 1465, 1450, 1300, 1210, 1030, 705cm⁻¹.

Example 45 3-Benzhydryl-1-(3,4-dimethoxybenzyl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was obtained as an oil.

¹H-NMR (CDCl₃) δ: 2.30-2.90 (m, 6H), 3.30-3.45 (m, 1H), 3.35 and 3.49(ABq, 2H, J=13 Hz), 3.88, 3.91 (each s, 6H), 4.60 (d, 1H, J=11.4 Hz),6.75-7.32 (m, 13H).

To the above oil, ethanol and a calculated amount of conc. hydrochloricacid were added, and the solvent was distilled off under reducedpressure. Ethyl ether was added to the residue, and the resultingcrystalline powder was collected by filtration to obtain thehydrochloride of the title compound (yield: 73%).

mp 174-180° C.

IR (KBr) 2950, 2450, 2360, 1720, 1590, 1515, 1445, 1265, 1230, 1145,1015, 700 cm⁻¹.

Example 46 3-Benzhydryl-1-(3,4,5-trimethoxybenzyl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was obtained as an oil (yield: 81%).

¹H-NMR (CDCl₃) δ: 2.40-2.90 (m, 6H), 3.30-3.45 (m, 1H), 3.43 and 3.56(ABq, 2H, J=13 Hz), 3.85, 3.87 (each s, 9H), 4.56 (d, 1H, J=11 Hz),7.05-7.35 (m, 12H).

To the above oil were added ethanol and a calculated amount of conc.hydrochloric acid, and the solvent was distilled off under reducedpressure. Ethyl ether was added to the residue, and the resultingcrystalline powder was collected by filtration to obtain the titlecompound.

mp 182-185° C.

IR (KBr) 2925, 2500, 1720, 1585, 1500, 1465, 1445, 1420, 1330, 1240,1180, 1160, 1120, 995, 850, 740, 700 cm⁻¹.

Example 473-Benzhydryl-1-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was obtained (yield: 48%).

mp 180-181° C.

IR (KBr) 3000, 2910, 2760, 1700, 1485, 1440, 1420, 1195, 1075, 760, 750,700 cm⁻¹.

Example 483-Benzhydryl-1-(5H-dibenzo[a,d]cyclohepten-5-yl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was obtained (yield: 88%).

mp 175-178° C.

IR (KBr) 3030, 2780, 1715, 1495, 1445, 1310, 1250, 1090, 810, 800, 775,750, 710, 550, 480 cm⁻¹.

Example 49 3-Benzhydryl-1-(4-methoxybenzyl)-4-piperidinone

According to the same manner as that described in Example 32, 0.85 g ofthe title compound was obtained (yield: 66%).

mp 103-104° C.

IR (KBr) 3025, 2950, 2780, 1710, 1610, 1510, 1240, 1030, 740, 700, 540cm⁻¹.

Example 50 3-Benzhydryl-1-(9H-xanthen-9-yl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was synthesized (yield: 39%).

mp 180-181° C.

IR (KBr) 3020, 2900, 2780, 1705, 1595, 1565, 1485, 1470, 1450, 1330,1320, 1250, 1200, 1190, 1180, 895, 760, 750, 695, 535 cm⁻¹.

Example 51 3-Benzhydryl-1-(9H-thioxanthen-9-yl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was synthesized (yield: 39%).

mp 186-188° C.

IR (KBr) 2940, 2800, 1715, 1590, 1500, 1475, 1440, 1335, 750, 710 cm⁻¹.

Example 52 3-Benzhydryl-1-cinnamyl-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was synthesized (yield: 61%).

mp 114-115° C.

IR (KBr) 3010, 2780, 1710, 1590, 1485, 1440, 1330, 1170, 1125, 1030,965, 735, 700, 685, 540 cm⁻¹.

Example 53 3-Benzhydryl-1-(pyridin-3-ylmethyl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was synthesized (yield: 40%).

mp 121-122° C.

IR (KBr) 3025, 2950, 2910, 2800, 1710, 1590, 1570, 1490, 1445, 1420,1345, 1185, 1085, 1025, 780, 700, 550 cm⁻¹.

Example 54 3-Benzhydryl-1-(pyridine-2-ylmethyl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was synthesized (yield: 36%).

mp 100° C.

IR (KBr) 3025, 2900, 2800, 1710, 1585, 1565, 1490, 1470, 1450, 1430,1340, 1185, 1080, 990, 780, 760, 740, 700, 690, 545, 490 cm⁻¹.

Example 55 3-Benzhydryl-1-[(3-hydroxypyridin-2-yl)methyl]-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was synthesized (yield: 61%).

mp 121-122° C.

IR (KBr) 3025, 2950, 2820, 1710, 1595, 1575, 1490, 1445, 1415, 1355,1335, 1260, 1235, 1220, 1165, 1115, 1090, 980, 800, 775, 740, 700, 690,540 cm⁻¹.

Example 563-Benzhydryl-1-[(3-hydroxy-6-methylpyridin-2-yl)methyl]-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was synthesized (yield: 78%).

mp 164-165° C.

IR (KBr) 3020, 2920, 2800, 2500, 1715, 1575, 1490, 1470, 1445, 1420,1340, 1300, 1275, 1190, 1165, 1125, 840, 740, 700, 635, 600, 540 cm⁻¹.

Example 57 3-Benzhydryl-1-(2-propargyl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was synthesized (yield: 20%).

mp 85-87° C.

IR (KBr) 3250, 3025, 2800, 2795, 1710, 1595, 1495, 1470, 1450, 1340,1315, 1195, 800, 780, 750, 700, 540 cm⁻¹.

Example 58 3-Benzhydryl-1-(1H-indol-3-ylmethyl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was synthesized (yield: 36%).

mp 170-171° C.

IR (KBr) 3270, 3050, 2800, 1700, 1490, 1450, 1435, 1350, 1240, 1195,1095, 1090, 1005, 740, 700, 545 cm⁻¹.

Example 59 3-Benzhydryl-1-(2-thienylmethyl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was synthesized as an oil (yield: 48%).

¹H-NMR (CDCl₃) δ: 2.27-2.95 (m, 6H), 3.33-3.45 (m, 1H), 3.67 and 3.76(ABq, 2H, J=14 Hz), 4.66 (d, 1H, J=11.2 Hz), 6.84-7.36 (m, 13H).

The above oil was dissolved in ethanol, conc. hydrochloric acid wasadded thereto, and the solvent was distilled off under reduced pressure.Ethyl ether was added to the residue, and the resulting crystallinepowder was collected by filtration to obtain the hydrochloride of thetitle compound.

mp 177-179° C.

IR (KBr) 3425, 3025, 2440, 2375, 1730, 1490, 1450, 1370, 855, 745, 700cm⁻¹.

Example 60 3-Benzhydryl-1-(2-furylmethyl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was synthesized as an oil (yield: 52%).

¹H-NMR (CDCl₃) δ: 2.30-2.90 (m, 6H), 3.35-3.45 (m, 1H), 3.46 and 3.63(ABq, 2H, J=14 Hz), 4.57 (d, 1H, J=10 Hz), 6.11-7.40 (m, 13H).

The above oil was dissolved in ethanol, conc. hydrochloric acid wasadded thereto, and the solvent was distilled off under reduced pressure.Ethyl ether was added to the residue, and the resulting crystallinepowder was collected by filtration to obtain the hydrochloride of thetitle compound.

mp 188-190° C.

IR (KBr) 3425, 2900, 2425, 2390, 1730, 1600, 1495, 1450, 1150, 1020,750, 700, 600, 545 cm⁻¹.

Example 613-Benzhydryl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4-piperidinone

According to the same manner as that described in Example 32, thesynthesis was carried out. Purification by silica gel columnchromatography (dichloromethane:methanol=4:1) gave the title compound(yield: 51%).

¹H-NMR (CDCl₃) δ: 2.11 (s, 3H), 2.50, 2.80 (each m, 6H), 3.30-3.55 (m,1H), 3.38 and 3.51 (ABq, 2H, J=13.6 Hz), 4.55 (d, 1H, J=11.4 Hz),7.00-7.46 (m, 11H).

The above oil was dissolved in ethanol, conc. hydrochloric acid wasadded thereto, and the solvent was distilled off under reduced pressure.Ethyl ether was added to the residue, and the resulting crystallinepowder was collected by filtration to obtain the hydrochloride of thetitle compound.

mp 172-174° C.

IR (KBr) 3450, 3000, 2650, 1720, 1640, 1490, 1450, 1370, 1190, 745, 700,690, 630, 635 cm⁻¹.

Example 623-Benzhydryl-1-[(E)-3-(2-methoxyphenyl)-2-propenyl]-4-piperidinone

To a solution of 1.62 g of 3-(2-methoxyphenyl)acrylaldehyde in 20 ml ofethanol was added 0.5 g of sodium borohydride, and the mixture wasstirred at room temperature for several hours. Then, 30 ml of ethylacetate was added and the mixture was washed three times with brine.After drying over magnesium sulfate, the solvent was distilled off underreduced pressure. The residue was dissolved in 20 ml of dichloromethane,and 3 g of 3-benzhydryl-4-piperidinone hydrochloride, 5.1 g ofdiisopropyl ethylamine and 2.4 ml of EPPA were added thereto withstirring under ice-cooling. After allowing to stand at room temperaturefor 16 hours, the solvent was distilled off under reduced pressure. Theresidue was subjected to silica gel column chromatography (100 g, ethylacetate:hexane=1:1) eluting with the same solvent. The desired fractionwas concentrated and precipitated crystals were triturated with ethylether and filtered to obtain 1.39 g of the title compound (yield: 34%).

mp 117-118° C.

IR (KBr) 2800, 1715, 1600, 1490, 1470, 1450, 1240, 1030, 755, 705, 545cm⁻¹.

Example 633-Benzhydryl-1-[2-(2-methoxyphenyl)ethaneimidoyl]-4-piperidinone

A solution of 3 g of 3-benzhydryl-4-piperidinone hydrochloride, 3.5 g ofethyl(2-methoxyphenyl)acetoimidate hydrochloride and 3.5 ml oftriethylamine in 20 ml of dichloromethane was stirred at 40° C. for 16hours. After washing with water and drying over magnesium sulfate, thesolvent was distilled off under reduced pressure. The residue waspurified by subjecting it to silica gel column chromatography (100 g,dichloromethane:methanol:trimethylamine=8:2:1). The solvent wasdistilled off, and the residue (crystal) was triturated with ethyl etherand filtered to obtain 0.78 g of the title compound (yield: 19%).

mp 57-58° C.

IR (KBr) 3400, 3300, 3000, 1715, 1580, 1490, 1465, 1450, 1250, 1110,1020, 760, 705 cm⁻¹.

Example 643-[Bis(4-chlorophenyl)methyl]-1-[2-(2-methoxyphenyl)ethaneimidoyl]-4-piperidinone

A solution of 1 g of 3-[bis(4-chlorophenyl)methyl-4-piperidinonehydrochloride, 0.8 g of ethyl2-methoxyphenylacetoimidate hydrochlorideand 1 ml of triethylamine in 10 ml of dichloromethane was refluxed for48 hours. After washing with water and drying over magnesium sulfate,the solvent was distilled off under reduced pressure. The residue waspurified by subjecting it to silica gel column chromatography (100 g,dichloromethane:methanol:triethylamine=8:2:1). The solvent was distilledoff to obtain 0.38 g of the title compound as a powder (amorphous,yield: 29%).

IR (KBr) 2920, 1715, 1600, 1495, 1460, 1250, 1110, 1090, 1015, 795, 750,540 cm⁻¹.

Example 653-[Bis(4-fluorophenyl)methyl]-1-[2-(2-methoxyphenyl)ethaneimidoyl]-4-piperidinone

A solution of 1.5 g of 3-[bis(4-fluorophenyl)methyl]-4-piperidinonehydrochloride, 0.8 g of ethyl 2-methoxyphenylacetoimidate hydrochlorideand 1 ml of triethylamine in 10 ml of dichloromethane was refluxed for20 hours. After washing with water and drying over magnesium sulfate,the solvent was distilled off under reduced pressure. The residue waspurified by subjecting it to silica gel column chromatography (100 g,dichloromethane:methanol:triethylamine=8:2:1). The solvent was distilledoff to obtain 0.6 g of the title compound as a powder (yield: 30%).

IR (KBr) 2925, 2840, 1715, 1600, 1510, 1460, 1440, 1250, 1220, 1160,1105, 1050, 1030, 825, 755, 550, 530 cm⁻¹.

Example 663-Benzhydryl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-4-piperidinone

A solution of 1.5 g of 3-benzhydryl-4-piperidinone hydrochloride, 1.3 gof 5-chloro-3-methyl-1,2,4-thiazole and 1.4 ml of triethylamine in 10 mlof dichloromethane was allowed to stand at room temperature for 48hours. The reaction mixture was washed with water and then dried overmagnesium sulfate. The solvent was distilled off under reduced pressureand the residue (crystal) was triturated with ethyl ether and filteredto obtain 1.3 g of the title compound (yield: 72%).

mp 164-166° C.

IR (KBr) 2900, 2860, 1715, 1560, 1490, 1450, 1385, 1315, 795, 745, 705,540 cm⁻¹.

Example 67 N-[(3-Benzhydryl-4-oxo-1-piperidinyl)carbothioyl]benzamide

A solution of 3 g of 3-benzhydryl-4-piperidinone hydrochloride, 1.6 g ofbenzoylisothiocyanate and 1.4 ml of triethylamine in 30 ml ofdichloromethane was stirred at room temperature for 5 hours. The solventwas distilled off under reduced pressure. Water and ethyl ether wereadded to the residue to precipitate crystals. Filtration gave 4 g of thetitle compound (yield: 93%).

mp 168-169° C.

IR (KBr) 3200, 1725, 1700, 1600, 1530, 1455, 1430, 1240, 1170, 1150,855, 755, 720, 700, 655 cm⁻¹.

Example 68 3-Benzhydryl-4-oxo-1-piperidinecarboxamide

A solution of 1 g of 3-benzhydryl-4-piperidinone hydrochloride and 0.35g of potassium isocyanate in 20 ml of ethanol and 10 ml of water wasstirred at room temperature for 16 hours. Crystals precipitated werecollected by filtration to obtain 1 g of the title compound (yield:97%).

mp 88-89° C.

IR (KBr) 3540, 3380, 3220, 1705, 1675, 1615, 1585, 1495, 1480, 1450,1310, 1090, 710, 545 cm⁻¹.

Example 69 3-Benzhydryl-4-oxo-1-piperidinecarbothioamide

A solution of 3 g of 3-benzhydryl-4-piperidinone hydrochloride and 1.1 gof potassium isothiocyanate in 100 ml of ethanol was refluxed for 16hours. After the solvent was distilled off under reduced pressure, theresidue was extracted with ethyl acetate and then the extract was washedwith water. After drying over magnesium sulfate, the solvent wasdistilled off under reduced pressure. The residue was dissolved inethanol and allowed to stand. Crystals were collected by filtration toobtain 1.3 g of the title compound (yield: 40%).

mp 107° C.

IR (KBr) 3500, 3425, 3300, 3180, 1705, 1650, 1625, 1600, 1500, 1450,1395, 1370, 1310, 1090, 980, 705, 550 cm⁻¹.

Example 703-Benzhydryl-N-(2-methoxyphenyl)-4-oxo-1-piperidinecarboxamide

A solution of 3 g of 3-benzhydryl-4-piperidinone hydrochloride, 1.5 g oforthomethoxyphenylisocyanate and 1.4 ml of triethylamine in 30 ml ofdichloromethane was stirred at room temperature for 2 hours. The solventwas distilled off under reduced pressure, and water and hexane wereadded to the residue. Crystals precipitated were collected by filtrationto obtain 3.98 g of the title compound (yield: 96%).

mp 150-151° C.

IR (KBr) 3450, 3030, 1720, 1655, 1600, 1530, 1490, 1460, 1390, 1335,1295, 1250, 1210, 1115, 1020, 755, 710, 540 cm⁻¹.

Example 713-Benzhydryl-N-(2-methoxyphenyl)-4-oxo-1-piperidinecarbothioamide

A solution of 3 g of 3-benzhydryl-4-piperidinone hydrochloride, 1.65 gof orthomethoxyphenyl isothiocyanate and 1.4 ml of triethylamine in 30ml of dichloromethane was stirred at room temperature for 2 hours. Thereaction mixture was washed with water and dried over magnesium sulfate,and then the solvent was distilled off under reduced pressure to obtain3 g of the title compound as an amorphous powder (yield: 70%).

IR (KBr) 3390, 2925, 1720, 1600, 1500, 1450, 1330, 1240, 1110, 1020,745, 700, 540 cm⁻¹.

Example 72 3-(3-Benzhydryl-4-oxo-1-piperidinyl)propanenitrile

A solution of 1 g of 3-benzhydryl-4-piperidinone hydrochloride, 0.1 g ofacrylonitrile and 1.52 g of DBU in 10 ml of dichloromethane was stirredfor 3 hours. After the solvent was distilled off under reduced pressure,the residue was subjected to silica gel column chromatography (100 g,ethyl acetate) eluting with ethyl acetate. The solvent was distilled offunder reduced pressure to obtain the title compound as an oil.

¹H-NMR (CDCl₃) δ: 2.30-2.45, 2.55-2.84, 2.69-3.10, 3.35-3.50 (each m,11H), 4.65 (d, 1H, J=11.4 Hz), 7.10-7.40 (m, 10H).

The above oil was dissolved in ethanol, 0.3 ml of conc. hydrochloricacid was added thereto, and the solvent was distilled off under reducedpressure. Crystals were triturated with ethyl ether and filtered toobtain 0.6 g of the hydrochloride of the title compound (yield: 51%).

mp 163-166° C.

IR (KBr) 3000, 2300, 1730, 1595, 1495, 1450, 1410, 1380, 750, 705, 540cm⁻¹.

Example 73 3-Benzhydryl-4-oxopiperidine-1-sulfonate Sodium

A solution of 1 g of 3-benzhydryl-4-piperidinone hydrochloride, 1.5 g ofpyridine sulfuric acid complex and 0.6 ml of diisopropyl ethylamine in 5ml of dimethylformamide was stirred for 1 hour. Then, 30 ml of 1 Naqueous solution of sodium hydroxide was added thereto underice-cooling, and the mixture was applied to Amberite XAD-2 column andeluted with water and then methanol. The yellow solution of the desiredfraction was concentrated under reduced pressure. After the residue wascrystallized, it was lyophilized to obtain 1.1 g of the title compound(yield: 90%).

mp 136-140° C.

IR (KBr) 3450, 3025, 2830, 1710, 1625, 1595, 1560, 1230, 1190, 1040,980, 920, 740, 700, 630, 610, 540 cm⁻¹.

Example 74N-[(E)-1-[(3-Benzhydryl-4-oxo-1-piperidinyl)carbonyl]-2-(3-piperidinyl)ethenyl]acetamide

A solution of 3 g of 3-benzhydryl-4-piperidinone hydrochloride, 1.9 g of2-methyl-4-(3-pyridylmethylidene)-5-oxazolone and 1.4 ml oftriethylamine in 10 ml of dimethylformamide was stirred at roomtemperature for 5 hours. After addition of 30 ml of water and stirringat room temperature for 16 hours, crystals precipitated were collectedby filtration and washed with a small amount of ethanol and then ethylether to obtain 2 g of the title compound (yield: 44%).

mp 224-225° C.

IR (KBr) 3550, 3280, 3020, 1710, 1680, 1660, 1640, 1515, 1430, 1370,1300, 1280, 1265, 860, 750, 705, 540 cm⁻¹.

Example 753-[Bis(4-fluorophenyl)methyl]-1-(2-hydroxybenzyl)-4-piperidinone

According to the same manner as that described in Example 38, the titlecompound was obtained (yield: 81%).

mp 151-152° C.

IR (KBr) 2820, 1710, 1600, 1585, 1500, 1485, 1460, 1350, 1315, 1230,1220, 1190, 1155, 825, 760, 545, 475 cm⁻¹.

Example 763-[Bis(4-fluorophenyl)methyl]-1-(5-bromo-2-methoxybenzyl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was synthesized (yield: 66%).

mp 129-130° C.

IR (KBr) 2775, 1705, 1600, 1515, 1485, 1440, 1250, 1220, 1155, 1115,1030, 825, 795, 620, 560, 550, 525 cm⁻¹.

Example 773-[Bis(4-fluorophenyl)methyl]-1-(3-methoxybenzyl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was obtained as an oil.

¹H-NMR (CDCl₃) δ: 2.25-2.95 (m, 6H), 3.26 (m, 1H), 3.40 and 3.54 (ABq,2H, J=13 Hz), 3.83 (s, 3H, OMe), 4.59 (d, 1H, J=11 Hz), 6.75-7.85 (m,12H).

The above oil was dissolved in ethanol, a calculated amount of conc.hydrochloric acid was added thereto, and the solvent was distilled offunder reduced pressure. To the residue was added ethyl ether, themixture was stirred for 16 hours, and then the resulting powder wascollected by filtration and dried to obtain the hydrochloride of thetitle compound (yield: 67%).

mp 161-163° C.

IR (KBr) 2925, 2600, 2550, 1730, 1600, 1585, 1505, 1490, 1445, 1440,1270, 1220, 1180, 1160, 1050, 830, 785, 695, 545 cm⁻¹.

Example 783-[Bis(4-fluorophenyl)methyl]-1-(2,3,4-trimethoxybenzyl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was obtained as an oil.

¹H-NMR (CDCl₃) δ: 2.25-2.95 (m, 6H), 3.20 (m, 1H), 3.31 and 3.53 (ABq,2H, J=13 Hz), 2.85 (s, 3H), 3.88 (s, 6H), 4.55 (d, 1H, J=11 Hz),6.58-7.26 (m, 10H).

The above oil was dissolved in ethanol, a calculated amount of conc.hydrochloric acid was added thereto, and the solvent was distilled offunder reduced pressure. To the residue was added ethyl ether, themixture was stirred for 16 hours, and then the resulting powder wascollected by filtration and dried to obtain the hydrochloride of thetitle compound (yield: 64%).

mp 174-176° C.

IR (KBr) 2925, 2460, 1600, 1505, 1470, 1420, 1280, 1225, 1160, 1100,1010, 825, 800, 550 cm⁻¹.

Example 793-[(4-Fluorophenyl)(phenyl)methyl]-1-(2-methoxybenzyl)-4-piperidinone

To a solution of 1 g of 1-(2-methoxybenzyl)-4-piperidinone in 20 ml ofdichloromethane was added 2 ml of TMSOTf under ice-cooling. Then, 1 g of4-fluorobenzhydrol was added and the mixture was stirred at roomtemperature for 16 hours. Then, 20 ml of water was added thereto, andthe mixture was neutralized with sodium bicarbonate. The dichloromethanelayer was dried over magnesium sulfate, and the solvent was distilledoff under reduced pressure. The residue (crystal) was triturated withhexane and filtered to obtain 0.45 g of the title compound (yield: 22%).

mp 115-116° C.

IR (KBr) 2800, 1710, 1600, 1505, 1495, 1245, 1220, 1030, 810 cm⁻¹.

Example 803-[Bis(4-fluorophenyl)methyl]-1-[3,5-bis(trifluoromethyl)benzyl]-4-piperidinone

(Step 1)

To 10 ml of dimethylformamide were added 2.33 g of 4-piperidinoneethyleneketal, 5 g of 3,5-bis(trifluoromethyl)benzyl bromide and 2.25 gof potassium carbonate with stirring. After completion of an exothermicreaction, the mixture was stirred in an oil bath at 65° C. for 60minutes. The mixture was extracted with 30 ml of ethyl acetate and theextract was washed with water, and then the solvent was distilled offunder reduced pressure. To the residue were added 20 ml of water, 20 mlof acetone and 2.7 ml of conc. hydrochloric acid, and the mixture wasstirred in an oil bath at 65° C. for 16 hours. After cooling, 30 ml ofdichloromethane was added and the mixture was neutralized with sodiumbicarbonate. The dichloromethane layer was dried over magnesium sulfate,and the solvent was distilled off under reduced pressure to obtain 3.8 gof 1-[3,5-bis(trifluoromethyl)benzyl]-4-piperidinone (yield: 72%).

¹H-NMR (CDCl₃) δ: 2.50 (t, 4H, J=6 Hz), 2.79 (t, 4H, J=6 Hz), 3.74 (s,2H), 7.70-7.90 (m, 3H).

(Step 2)

To a solution of 1.4 g of1-[3,5-bis(trifluoromethyl)benzyl]-4-piperidinone obtained in Step 1 in15 ml of dichloromethane was added 2 ml of TMSOTf under ice-cooling.Then, 1,1 g of 4,4′-difluorobenzhydrol was added thereto and the mixturewas stirred at room temperature for 16 hours. To this was added 20 ml ofwater and the mixture was neutralized with sodium carbonate. Thedichloromethane layer was dried over magnesium sulfate, and the solventwas distilled off under reduced pressure. The residue (crystal) wastriturated with hexane and filtered to obtain 1.4 g of the titlecompound. Recrystallization from a small amount of hot ethyl acetategave 0.97 g (yield: 37%).

mp 205-206° C.

IR (KBr) 2800, 1710, 1505, 1350, 1280, 1220, 1170, 1120, 885, 830, 700,680, 555, 525 cm⁻¹.

Example 813-Benzhydryl-1-[3,5-bis(trifluoromethyl)benzyl]-4-piperidinone

According to the same manner as that described in Example 80, the titlecompound was obtained (yield: 44%).

mp 180-182° C.

IR (KBr) 2960, 2800, 1710, 1495, 1450, 1355, 1345, 1280, 1170, 1120,880, 750, 700, 680, 545 cm⁻¹.

Example 823-[Bis(4-fluorophenyl)methyl]-1-(2-fluorobenzyl)-4-piperidinone

According to the same manner as that described in Example 80, the titlecompound was obtained as an oil (yield: 56%).

¹H-NMR (CDCl₃) δ: 2.25-3.00 (m, 6H), 3.20 (m, 1H), 3.51 and 3.60 (ABq,2H, J=13 Hz), 4.59 (d, 1H, J=11 Hz), 6.75-7.35 (m, 12H).

The above oil was dissolved in ethyl ether, and a calculated amount of asolution of 4 N Cl/dioxane was added thereto. Crystals precipitated werecollected by filtration to obtain the hydrochloride of the titlecompound.

mp 162-164° C.

IR (KBr) 2990, 2525, 1730, 1600, 1505, 1455, 1415, 1220, 1185, 1155,1115, 880, 760, 550 cm⁻¹.

Example 83 3-Benzhydryl-1-(2-fluorobenzyl)-4-piperidinone

According to the same manner as that described in Example 80, thehydrochloride of the title compound was obtained (yield: 50%).

mp 165-166° C.

IR (KBr) 1730, 1620, 1585, 1495, 1450, 1240, 1190, 1110, 1030, 760, 740,700 cm⁻¹.

Example 843-[Bis(4-fluorophenyl)methyl]-1-[2-(2-methoxyphenyl)-2-oxoethyl]-4-piperidinone

To 10 ml of dimethylformamide were added 1.1 g of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 0.8 g of2-bromo-2′-methoxyacetophenone and 1.4 g of potassium carbonate and themixture was stirred at room temperature for 16 hours. After dissolvingin 30 ml of ethyl acetate, the mixture was washed with water, and thendried over magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was recrystallized from ethyl acetate toobtain 0.88 g of the title compound (yield: 59%).

mp 148-149° C.

IR (KBr) 2975, 2910, 2850, 1710, 1660, 1595, 1510, 1290, 1250, 1220,1165, 830, 765, 560, 530 cm⁻¹.

Example 853-[Bis(4-fluorophenyl)methyl]-1-(2-fluoromethoxybenzyl)-4-piperidinone

To 5 ml of dimethylformamide were added 1 g of3-[bis(4-fluorophenyl)methyl]-1-(2-hydroxybenzyl)-4-piperidinone, 1 mlof 2.75 M solution of bromofluoromethane dichloromethane, 0.5 g ofpotassium carbonate and 0.48 ml of diisopropylethylamine, and themixture was stirred at room temperature for 26 hours. After dissolvingin 30 ml of ethyl acetate, the mixture was washed with water, and thendried over magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was subjected to silica gel columnchromatography (40 g, ethyl acetate:hexane=1:1) to obtain 1.2 g of thetitle compound as an oil.

¹H-NMR (CDCl₃) δ: 2.30-3.00 (m, 6H), 3.25 (m, 1H), 3.52 and 3.62 (ABq,J=13.3 Hz), 4.58 (d, 1H, J=11 Hz), 5.70 (d, 2H, J=54.6 Hz), 6.80-7.35(m, 12H).

The above oil was dissolved in 10 ml of ethyl ether, and 0.65 ml of asolution of 4 N HCl/dioxane was added thereto. The solvent was distilledoff under reduced pressure. To the residue was added ethyl ether toobtain 1.2 g (quantitative) of the hydrochloride of the title compoundas a powder (amorphous).

IR (KBr) 1730, 1605, 1510, 1460, 1420, 1235, 1160, 1130, 1080, 980, 830,760 cm⁻¹.

Example 863-[Bis(4-fluorophenyl)methyl]-1-(2-isopropoxybenzyl)-4-piperidinone

To 5 ml of dimethylformamide were added 1 g of3-[bis(4-fluorophenyl)methyl]-1-(2-hydroxybenzyl)-4-piperidinone, 1.3 mlof isopropyl iodide and 2.8 g of potassium carbonate and the mixture wasstirred in an oil bath at 100° C. for 16 hours. The solvent was replacedwith 30 ml of ethyl acetate, the solution was washed with water, andthen dried over magnesium sulfate, and the solvent was distilled offunder reduced pressure. The residue was purified by subjecting it to asilica gel column chromatography (40 g, ethyl acetate:hexane=1:1). Theresidue (crystal) was triturated with hexane and filtered to obtain 0.35g of the title compound (yield: 31%).

mp 155-156° C.

IR (KBr) 2975, 2810, 1710, 1605, 1510, 1490, 1245, 1220, 1115, 960, 835,760, 560, 530 cm⁻¹.

Example 873-[Bis(4-fluorophenyl)methyl]-1-(pyridin-3-ylmethyl)-4-piperidinone

To 7 ml of dimethylformamide were added 1.1 g of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 0.66 g of3-chloromethylpyridine hydrochloride, 1.4 g of potassium carbonate andthe mixture was stirred at room temperature for 7 hours. The mixture wasextracted with 30 ml of ethyl acetate, the extract was washed withwater, and then dried over magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified bysubjecting it to silica gel column chromatography (40 g, ethylacetate:hexane=1:1) to obtain 1 g of the title compound as an oil.

¹H-NMR (CDCl₃) δ: 2.30-2.95 (m, 6H), 3.27 (m, 1H), 3.42 and 3.58 (ABq,2H, J=13.3 Hz), 4.57 (d, 1H, J=11.3 Hz), 6.80-7.30, 7.58, 8.55 (each m,12H).

The above oil was dissolved in ethyl ether and 1.3 ml of a solution of 4N HCl/dioxane was added thereto to obtain 1 g of the hydrochloride ofthe title compound as a powder (amorphous, yield: 68%).

IR (KBr) 3425, 1730, 1605, 1510, 1225, 1130, 835 cm⁻¹.

Example 883-[Bis(4-fluorophenyl)methyl]-1-[[2-(2-diethylamino)ethoxy]benzyl]-4-piperidinone

To 10 ml of dimethylformamide were added 1 g of3-[bis(4-fluorophenyl)methyl]-1-(2-hydroxybenzyl)-4-piperidinone, 1.7 gof diethylaminoethyl chloride hydrochloride and 2.8 g of potassiumcarbonate and the mixture was stirred in an oil bath at 90° C. for 7hours. The mixture was extracted with 30 ml of ethyl acetate, theextract was washed with water, and dried over magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by subjecting it to silica gel column chromatography (40 g,ethyl acetate:methanol=4:1) to obtain 0.7 g of the title compound as anoil.

¹H-NMR (CDCl₃) δ: 1.07 (t, 6H, J=7.2 Hz), 2.35-3.00 (m, 6H), 2.64 (q,4H, J=7.2 Hz), 2.83 (t, 2H, J=6.2 Hz), 3.28 (m, 1H), 3.48 and 3.64 (ABq,2H, J=13.2 Hz), 4.02 (t, 2H, J=6.2 Hz), 4.57 (d, 1H, J=11.4 Hz),6.80-7.29 (m, 12H).

The above oil was dissolved in ethyl ether and 1.3 ml of a solution of 4N HCl/dioxane thereto to obtain the hydrochloride of the title compoundas a powder (amorphous, yield: 48%).

IR (KBr) 3450, 1730, 1605, 1510, 1460, 1225, 1160, 1120, 840, 760 cm⁻¹.

Example 893-[Bis(4-fluorophenyl)methyl]-1-[(3,5-dimethylisooxazol-4-yl)methyl]-4-piperidinone

To 10 ml of dimethylformamide were added 1.1 g of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 0.5 g of4-chloromethyl-3,5-dimethylisooxazole and 1.4 g of potassium carbonateand the mixture was stirred at room temperature for 16 hours. Themixture was extracted with 30 ml of ethyl acetate, the extract waswashed with water, and dried over magnesium sulfate, and the solvent wasdistilled off under reduced pressure to obtain the title compound as anoil.

¹H-NMR (CDCl₃) δ: 2.22, 2.32 (each s, 6H), 2.30-2.70 (m, 6H), 2.80 (m,1H), 3.19 (s, 2H), 4.50 (d, 1H, J=11 Hz), 6.89-7.26 (m, 8H).

The above oil was dissolved in ethyl ether and 1 ml of a solution of 4 NHCl/dioxane was added thereto to obtain 1.2 g of the hydrochloride ofthe title compound as a crystalline powder (yield: 81%).

mp 114-116° C.

IR (KBr) 3450, 1730, 1630, 1605, 1510, 1420, 1230, 1160, 830, 555 cm⁻¹.

Example 903-[Bis(4-fluorophenyl)methyl]-1-(quinolin-2-ylmethyl)-4-piperidinone

To 10 ml of dimethylformamide were added 1.1 g of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 0.8 g of2-chloromethylquinoline hydrochloride and 2.8 g of potassium carbonateand the mixture was stirred at room temperature for 16 hours. Themixture was extracted with 30 ml of ethyl acetate, the extract waswashed with water, and dried over magnesium sulfate, and the solvent wasconcentrated under reduced pressure. Crystals precipitated werecollected by filtration to obtain 1.1 g of the title compound (yield:73%).

mp 188-189° C.

IR (KBr) 2820, 1705, 1600, 1510, 1345, 1310, 1205, 1165, 1110, 855, 835,760, 555 cm⁻¹.

Example 91

3-[Bis(4-fluorophenyl)methyl]-1(4-trifluoromethylbenzyl)-4-piperidinone

According to the same manner as that described in Example 80, the titlecompound was obtained (yield: 33%).

mp 126-127° C.

IR (KBr) 2950, 2825, 1715, 1600, 1505, 1415, 1325, 1220, 1165, 1120,1065, 825, 545 cm⁻¹.

Example 92

3-Benzhydryl-1-(4-trifluoromethylbenzyl)-4-piperidinone

According to the same manner as that described in Example 80, the titlecompound was obtained as an oil.

¹H-NMR (CDCl₃) δ: 2.30-2.95 (m, 6H), 3.37 (m, 1H), 3.45 and 3.60 (ABq,2H, J=13 Hz), 4.60 (d, 1H, J=11.2 Hz), 7.08-7.57 (m, 14H).

The above oil was dissolved in ethyl ether, a calculated amount of asolution of 4 N HCl/dioxane was added thereto, and the mixture wasstirred. Crystals were collected by filtration to obtain thehydrochloride of the title compound (yield: 52%).

mp 168-169° C.

IR (KBr) 2500, 1735, 1495, 1455, 1420, 1330, 1165, 1130, 1070, 700 cm⁻¹.

Example 933-[Bis(4-fluorophenyl)methyl]-1(3-trifluoromethylbenzyl)-4-piperidinone

According to the same manner as that described in Example 80, the titlecompound was obtained (yield: 43%).

mp 150-151° C.

IR (KBr) 2950, 2800, 1705, 1600, 1510, 1450, 1330, 1225, 1170, 1160,1120, 825, 785, 700, 660, 560, 525 cm⁻¹.

Example 94 3-Benzhydryl-1-(3-trifluoromethylbenzyl)-4-piperidinone

According to the same manner as that described in Example 80, the titlecompound was obtained (yield: 25%).

mp 128-129° C.

IR (KBr) 1700, 1490, 1450, 1325, 1160, 1115, 1070, 785, 740, 700, 545cm⁻¹.

Example 953-[Bis(4-fluorophenyl)methyl]-1(2-trifluoromethylbenzyl)-4-piperidinone

According to the same manner as that described in Example 80, the titlecompound was obtained (yield: 75%).

mp 102-103° C.

IR (KBr) 2900, 1700, 1605, 1510, 1450, 1380, 1340, 1315, 1255, 1220,1155, 1115, 1035, 1025, 825, 765, 725, 560, 530.

Example 96 3-Benzhydryl-1-(2-trifluoromethylbenzyl)-4-piperidinone

According to the same manner as that described in Example 80, the titlecompound was obtained (yield: 60%).

¹H-NMR (CDCl₃) δ: 2.30-2.95 (m, 6H), 3.38 (m, 1H), 3.60 and 3.72 (ABq,2H, J=14 Hz), 4.64 (d, 1H, J=11.2 Hz), 7.09-1.74 (m, 14H).

The above oil was dissolved in ethyl ether and a calculated amount of asolution of 4 N HCl/dioxane was added thereto. The solvent was distilledoff under reduced pressure, and ethyl ether was added to the crystallineresidue and crystals were collected by filtration to obtain thehydrochloride of the title compound.

mp 138-140° C.

IR (KBr) 2480, 1730, 1495, 1455, 1315, 1180, 1120, 1040, 775, 705, 545cm⁻¹.

Example 973-[Bis(4-fluorophenyl)methyl]-1-[2-(2-methylpropoxy)benzyl]-4-piperidionone

To 10 ml of dimethylformamide were added 1 g of3-[Bis(4-fluorophenyl)methyl]-1-(2-hydroxybenzyl)-4-piperidinone, 0.9 gof isobutyl iodide and 0.7 g of potassium carbonate and the mixture wasstirred in an oil bath at 70° C. for 16 hours. The mixture was extractedwith 30 ml of ethyl acetate, the extract was washed with water, and thendried over magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was dissolved in hexane, and crystalsprecipitated were collected by filtration to obtain 0.9 g of the titlecompound (yield: 78%).

mp 143-144° C.

IR (KBr) 2960, 1710, 1600, 1505, 1240, 1220, 1160, 1105, 1030, 830, 760,525 cm⁻¹.

Example 983-[Bis(4-fluorophenyl)methyl]-1-(2-ethoxybenzyl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was obtained (yield: 59%).

mp 137-138° C.

IR (KBr) 2975, 2800, 1710, 1600, 1505, 1240, 1220, 1120, 1045, 830, 760,560, 525 cm⁻¹.

Example 99 3-Benzhydryl-1-(2-ethoxybenzyl)-4-piperidinone

According to the same manner as that described in Example 32, the titlecompound was obtained as an oil.

¹H-NMR (CDCl₃) δ: 1.33 (t, J=7 Hz), 2.30-2.95 (m, 6H), 3.40 (m, 1H),3.54 and 3.64 (ABq, 2H), 4.62 (d, J=11.2 Hz), 6.80-7.35 (m, 14H)

The above oil was dissolved in ethyl ether and a calculated amount of asolution of 4 N HCl/dioxane was added thereto. Crystals precipitatedwere collected by filtration to obtain the hydrochloride of the titlecompound (yield: 72%).

mp 172-174° C.

IR (KBr) 2980, 2925, 2490, 1730, 1605, 1500, 1455, 1260, 1130, 1045,765, 750, 710, 545 cm⁻¹.

Example 1003-[Bis(4-fluorophenyl)methyl]-1-(2-hydroxy-5-nitrobenzyl)-4-piperidinone

To 10 ml of dimethylformamide were added 1.1 g of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 0.7 g of2-chloromethyl-4-nitrophenol and 1.4 g of potassium carbonate and themixture was stirred at 70° C. for 3 hours. The mixture was extractedwith 30 ml of ethyl acetate, the extract was washed with water, and theethyl acetate was distilled off under reduced pressure. The residue wasdissolved in a small amount of ethyl ether and allowed to stand.Crystals precipitated were collected by filtration to obtain 0.64 g ofthe title compound (yield: 42%).

mp 169-170° C.

IR (KBr) 2840, 1715, 1615, 1600, 1580, 1500, 1475, 1450, 1335, 1280,1215, 1160, 1085, 820, 745, 525 cm⁻¹.

Example 1012-[[3-[Bis(4-fluorophenyl)methyl]-4-oxopiperidin-1-yl]methyl]benzonitrile

To 10 ml of dimethylformamide were added 1.1 g of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 0.7 g of2-cyanobenzylbromide and 1.4 g of potassium carbonate and the mixturewas stirred at room temperature for 16 hours. The mixture was extractedwith 30 ml of ethyl acetate, the extract was washed with water, and thendried over magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (40 g, ethyl acetate:hexane=1:1). Crystals weretriturated with hexane and filtered to obtain 0.92 g of the titlecompound (yield: 66%).

mp 83-84° C.

IR (KBr) 2900, 2210, 1710, 1700, 1600, 1505, 1440, 1340, 1275, 1220,1200, 1155, 1030, 1000, 620, 555, 520 cm⁻¹.

Example 1023-[[3-[Bis(4-fluorophenyl)methyl]-4-oxopiperidin-1-yl]methyl]benzonitrile

To 10 ml of dimethylformamide were added 1.1 g of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 0.7 g of3-cyanobenzylbromide and 1.4 g of potassium carbonate and the mixturewas stirred at room temperature for 16 hours. The mixture was extractedwith 30 ml of ethyl acetate, the extract was washed with water, and thendried over magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was dissolved in 5 ml of hot ethanol, andthen ice-cooled. Crystals precipitated were collected by filtration toobtain 1.18 g of the title compound (yield: 85%).

mp 159-160° C.

IR (KBr) 2950, 2790, 2740, 2225, 1705, 1600, 1505, 1355, 1295, 1220,1155, 825, 780, 685, 570, 550, 525 cm⁻¹.

Example 1034-[[3-[Bis(4-fluorophenyl)methyl]-4-oxopiperidin-1-yl]methyl]benzonitrile

To 10 ml of dimethylformamide were added 1.1 g of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 0.7 g of4-cyanobenzyl bromide and 1.4 g of potassium carbonate and the mixturewas stirred at room temperature for 16 hours. The mixture was extractedwith 30 ml of ethyl acetate, the extract was washed with water, and thendried over magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (40 g, ethyl acetate:hexane=1:1). Crystals weretriturated with hexane and filtered to obtain 1 g of the title compound(yield: 72%).

mp 118-120° C.

IR (KBr) 2800, 2225, 1710, 1600, 1505, 1465, 1410, 1340, 1220, 1155,1100, 1015, 990, 830, 790, 550 cm⁻¹.

Example 1041-(1,1′-Biphenyl-4-ylmethyl)-3-[bis(4-fluorophenyl)methyl]-4-piperidinone

According to the same manner as that described in Example 102, the titlecompound was obtained using 4-phenylbenzyl chloride (yield: 73%).

mp 148-149° C.

IR (KBr) 2800, 1705, 1600, 1500, 1340, 1220, 1155, 1100, 825, 770, 735,695, 545, 520 cm⁻¹.

Example 1053-[Bis(4-fluorophenyl)methyl]-1-(2,6-dichlorobenzyl)-4-piperidinone

According to the same manner as that described in Example 102, the titlecompound was obtained using 2,6-dichlorobenzyl bromide (yield: 75%).

mp 137-138° C.

IR (KBr) 2800, 1715, 1600, 1500, 1435, 1215, 825, 765 cm⁻¹.

Example 1063-[Bis(4-fluorophenyl)methyl]-1-(4-hydroxybenzyl)-4-piperidinone

To 10 ml of dichloromethane were added 1.1 g of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 1.7 ml ofdiisopropylethylamine and 0.5 g of p-hydroxybenzyl alcohol were added,and then 1 ml EPPA was added there to at room temperature. Afterstirring for 16 hours, the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(40 g ethyl acetate:hexane=1:1) to obtain the title compound as an oil.

¹H-NMR (CDCl₃) δ: 2.30-2.90 (m, 6H), 3.25 (m, 1H), 3.34 and 3.50 (ABq,2H, J=13 Hz), 4.58 (d, 1H, J=11 Hz), 6.75-7.27 (m, 12H).

The above oil was dissolved in 50 ml of ethyl ether, and 1 ml of asolution of 4 N HCl/dioxane was added thereto. The crystalline powderwas collected by filtration to obtain 1.2 g of the hydrochloride of thetitle compound (yield: 81%).

mp 145-146° C.

IR (KBr) 3200, 2950, 2550, 1730, 1615, 1510, 1450, 1415, 1270, 1220,1155, 825, 550, 525 cm⁻¹.

Example 1073-[Bis(4-chlorophenyl)methyl]-1-(4-hydroxybenzyl)-4-piperidinone

According to the same manner as that described in Example 106, the titlecompound was obtained as an oil using3-[bis(4-chlorophenyl)methyl]-4-piperidinone hydrochloride.

¹H-NMR (CDCl₃) δ: 2.30-2.90 (m, 6H), 3.25 (m, 1H), 3.33 and 3.50 (ABq,2H, J=12.8 Hz), 4.53 (d, 1H, J=11 Hz), 6.75-7.27 (m, 12H).

The above oil was dissolved in ethyl ether, and a calculated amount of asolution of 4 N HCl/dioxane was added thereto. The crystalline powderwas collected by filtration to obtain the hydrochloride of the titlecompound (yield: 69%).

mp 142-143° C.

IR (KBr) 3200, 2550, 1730, 1610, 1590, 1515, 1490, 1450, 1410, 1270,1230, 1175, 1090, 1010, 840, 820, 790, 540, 500 cm⁻¹.

Example 1083-[Bis(4-fluorophenyl)methyl]-1-(3-phenoxybenzyl)-4-piperidinone

To 10 ml of dichloromethane were added 1.1 g of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 1.7 ml ofdiisopropylethylamine and 0.7 g of 3-phenoxybenzyl alcohol, and then 1ml of EPPA was added thereto at room temperature. After allowing tostand at room temperature for 4 days, the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (40 g, ethyl acetate:hexane=1:1) to obtain the titlecompound as an oil.

¹H-NMR (CDCl₃) δ: 2.25-2.95 (m, 6H), 3.25 (m, 1H), 3.40 and 3.53 (ABq,2H, J=13.2 Hz), 4.58 (d, 1H, J=11 Hz), 6.83-7.41 (m, 17H).

The above oil was dissolved in 50 ml of ethyl ether, and 2 ml of asolution of 4 N HCl/dioxane was added thereto. The crystalline powderwas collected by filtration to obtain 1.1 g of the hydrochloride of thetitle compound (yield: 63%).

mp 164-165° C.

IR (KBr) 3425, 2950, 2500, 1730, 1600, 1580, 1510, 1485, 1440, 1260,1220, 1160, 830, 780, 690, 540 cm⁻¹.

Example 109 3-Benzhydryl-1-(3-phenoxybenzyl)-4-piperidinone

According to the same manner as that described in Example 108, the titlecompound was obtained as an oil using 3-benzhydryl-4-piperidinonehydrochloride.

¹H-NMR (CDCl₃) δ: 2.25-2.95 (m, 6H), 3.35 (m, 1H), 3.41 and 3.50 (ABq,2H, J=13 Hz), 4.61 (d, 1H, J=11.4 Hz), 6.89-7.41 (m, 19H).

The above oil was dissolved in ethyl ether and a calculated amount of asolution of 4 N HCl/dioxane was added thereto. The crystalline powderwas collected by filtration to obtain the hydrochloride of the titlecompound (yield: 62%).

mp 166-167° C.

IR (KBr) 2500, 1730, 1580, 1490, 1450, 1400, 1255, 1215, 745, 700, 540cm⁻¹.

Example 1103-[Bis(4-fluorophenyl)methyl]-1-[2,4-bis(trifluoromethyl)benzyl]-4-piperidinone

To 10 ml of dimethylformamide were added 1.1 g of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 1 g of2,4-bis(trifluoromethyl)benzyl bromide and 1.4 g of potassium carbonatewere added and the mixture was stirred at room temperature for 10 hours.The mixture was extracted with 30 ml of ethyl acetate, the extract waswashed with water, and then dried over magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue (crystal)was triturated with hexane and filtered to obtain 1 g of the titlecompound (yield: 57%).

mp 104-105° C.

IR (KBr) 2950, 2875, 1700, 1625, 1600, 1510, 1345, 1275, 1255, 1220,1170, 1155, 1025, 1085, 1050, 1030, 1000, 905, 840, 820, 780, 765, 560,525 cm⁻¹.

Example 111 3-Benzhydryl-1-(1,1′-biphenyl-4-ylmethyl)-4-piperidinone

According to the same manner as that described in Example 102, the titlecompound was obtained from 3-benzhydryl-4-piperidinone hydrochloride and4-phenylbenzyl chloride (yield: 70%).

mp 157-158° C.

IR (KBr) 3025, 2800, 1710, 1590, 1450, 1340, 1180, 765, 740, 705, 695,540 cm⁻¹.

Example 1123-[Bis(4-fluorophenyl)methyl]-1-(1,1′-biphenyl-2-ylmethyl)-4-piperidinone

To 10 ml of dimethylformamide were added 1.1 g of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 0.85 g of2-phenylbenzyl bromide and 1.4 g of potassium carbonate and the mixturewas stirred at room temperature for 7 hours. The mixture was extractedwith 30 ml of ethyl acetate, the extract was washed with water, and thendried over magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (40 g, ethyl acetate:hexane=1:1) to obtain the titlecompound as an oil.

¹H-NMR (CDCl₃) δ: 2.20-2.70 (m, 6H), 3.12 (m, 1H), 3.36 and 3.53 (ABq,2H, J=13.2 Hz), 4.48 (d, 1H, J=11 Hz), 6.78-7.45 (m, 17H).

The above oil was dissolved in 50 ml of ethyl ether and 1 ml of asolution of 4 N Cl/dioxane was added thereto. The crystalline powder wascollected by filtration to obtain 1.2 g of the hydrochloride of thetitle compound (yield: 71%).

mp 144-146° C.

IR (KBr) 2900, 2425, 2325, 1730, 1600, 1500, 1475, 1450, 1415, 1220,1155, 830, 775, 705, 575, 555, 515 cm⁻¹.

Example 113 3-Benzhydryl-1-(1,1′-biphenyl-2-ylmethyl)-4-piperidinone

According to the same manner as that described in Example 112, the titlecompound was obtained from 3-benzhydryl-4-piperidinone hydrochloride and2-phenylbenzyl chloride.

¹H-NMR (CDCl₃) δ: 2.20-2.70 (m, 6H), 3.25 (m, 1H), 3.36 and 3.51 (ABq,2H, J=13.5 Hz), 4.52 (d, 1H, J=11 Hz), 7.03-7.51 (m, 19H).

The above oil was dissolved in 50 ml of ethyl ether and 1 ml of asolution of 4 N HCl/dioxane was added thereto. The crystalline powderwas collected by filtration to obtain 1.2 g of the hydrochloride of thetitle compound (yield: 77%).

mp 146-148° C.

IR (KBr) 3050, 2275, 1730, 1595, 1490, 1480, 1450, 1410, 1385, 780, 760,745, 700, 540 cm⁻¹.

Example 1143-[Bis(4-fluorophenyl)methyl]-1-(2-nitrobenzyl)-4-piperidinone

To 10 ml of dimethylformamide were added 1.1 g of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 0.8 g of2-nitrobenzyl bromide and 1.4 g of potassium carbonate and the mixturewas stirred at room temperature for 7 hours. The mixture was extractedwith 30 ml of ethyl acetate and the extract was washed with water, andthe ethyl acetate was distilled off under reduced pressure. The residuewas dissolved in a small amount of ethanol and allowed to stand.Crystals precipitated were collected by filtration to obtain 1.2 g ofthe title compound (yield: 82%).

mp 151-152° C.

IR (KBr) 2800, 1705, 1600, 1530, 1500, 1465, 1360, 1215, 1185, 1155,820, 770, 720, 540 cm⁻¹.

Example 1153-[Bis(4-fluorophenyl)methyl]-1-(3-nitrobenzyl)-4-piperidinone

According to the same manner as that described in Example 114, the titlecompound was obtained from 3-[bis(4-fluorophenyl)methyl]-4-piperidinonehydrochloride and 3-nitrobenzyl bromide (yield: 89%).

mp 131-133° C.

IR (KBr) 2800, 1705, 1595, 1525, 1500, 1340, 1220, 1155, 820, 730, 690,540 cm⁻¹.

Example 1163-[Bis(4-fluorophenyl)methyl]-1-(4-nitrobenzyl)-4-piperidinone

To 10 ml of dimethylformamide were added 1.1 g of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 0.8 g of4-nitrobenzyl bromide and 1.4 g of potassium carbonate, and the mixturewas stirred at room temperature for 1 hour. The mixture was extractedwith 30 ml of ethyl acetate, the extract was washed with water, and thendried over magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by subjecting it to silicagel column chromatography (40 g, ethyl acetate). After addition ofethanol and allowing to stand, crystals precipitated were collected byfiltration to obtain 1 g of the title compound (yield: 69%).

mp 118-119° C.

IR (KBr) 2800, 1715, 1600, 1520, 1500, 1340, 1215, 1155, 1100, 840, 730,550, 545 cm⁻¹.

Example 1173-[Bis(4-methylphenyl)methyl]-1-(2-methoxybenzyl)-4-piperidinone

To a solution of 2.18 g of 1-(2-methoxybenzyl)-4-piperidinone in 20 mlof dichloromethane were added 4 ml of TMSOTf and then 2.12 g of4,4′-dimethylbenzhydrol under ice-cooling. After stirring at roomtemperature for 4 hours, 20 ml of water was added thereto and themixture was neutralized with sodium bicarbonate. The dichloromethanelayer was separated, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(40 g, ethyl acetate:hexane=1:4) to obtain 1.4 g of the title compoundas an oil.

¹H-NMR (CDCl₃) δ: 2.24 (s, 6H), 2.25-2.95 (m, 6H), 3.32 (m, 1H), 3.56(s, 2H), 3.77 (s, 3H), 4.56 (d, 1H, J=11.4 Hz), 6.83-7.33 (m, 11H).

The above oil was dissolved in 50 ml of ethyl ether, and 1.25 ml of asolution of 4 N HCl/dioxane was added thereto. The crystalline powderwas collected by filtration to obtain 1.35 g of the hydrochloride of thetitle compound (yield: 30%).

mp 161-164° C.

IR (KBr) 3400, 2900, 2500, 1725, 1600, 1510, 1495, 1460, 1250, 750, 550cm⁻¹.

Example 1183-[Bis(4-fluorophenyl)methyl]-1-(2,6-dimethoxybenzyl)-4-piperidinone

To 15 ml of dichloromethane were added 1.1 g of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 1.7 ml ofisopropyl ethylamine and 0.6 g of 2,6-dimethoxybenzyl alcohol and themixture was stirred at room temperature. Then, 0.8 ml of EPPA was addedthereto and the mixture was allowed to stand at room temperature for 4days. The solvent was distilled off under reduced pressure, and theresidue was purified by subjecting it to silica gel columnchromatography (40 g, ethyl acetate:hexane=1:1) to obtain 0.88 g of thetitle compound (yield: 60%).

mp 125-126° C.

IR (KBr) 1705, 1595, 1505, 1470, 1250, 1215, 1110, 830, 555, 525 cm⁻¹.

Example 1193-[Bis(4-fluorophenyl)methyl]-1-(2-difluoromethoxybenzyl)-4-piperidinone

To 15 ml of dichloromethane were added 1.1 g of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 1.7 ml ofisopropyl ethylamine and 0.6 g of 2-difluoromethoxybenzyl alcohol andthe mixture was stirred at room temperature. Then, 0.8 ml of EPPA wasadded thereto and the mixture was allowed to stand at room temperaturefor 5 days. After the solvent was distilled off under reduced pressure,the residue was purified by subjecting it to silica gel columnchromatography (40 g, ethyl acetate:hexane=1:1) to obtain 0.84 g of thetitle compound (yield: 55%).

mp 83-84° C.

IR (KBr) 2950, 2800, 1710, 1600, 1500, 1380, 1220, 1120, 1055, 830, 760,525 cm⁻¹.

Example 1203-[Bis(4-fluorophenyl)methyl]-1-(2-trifluoromethoxybenzyl)-4-piperidinone

To 15 ml of dichloromethane were added 1.1 g of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 1.7 ml ofisopropyl ethylamine and 0.7 g of 2-trofluoromethoxybenzyl alcohol andthe mixture was stirred at room temperature. Then, 0.81 ml of EPPA wasadded thereto and the mixture was allowed to stand at room temperaturefor 5 days. After the solvent was distilled off under reduced pressure,the residue was purified by silica gel column chromatography (40 g,ethyl acetate:hexane=1:1) to obtain 0.73 g of the title compound (yield:46%).

mp 88-89° C.

IR (KBr) 1710, 1600, 1505, 1250, 1215, 1170, 830, 760, 560, 525 cm⁻¹.

Example 121 3-Benzhydryl-1-(4-methylthiobenzyl)-4-piperidinone

To 15 ml of dichloromethane were added 1.1 g of3-benzhydryl-4-piperidinone hydrochloride, 1.7 ml of isopropylethylamine and 0.7 g of 4-methylthiobenzyl alcohol and the mixture wasstirred at room temperature. Then, 0.8 ml of EPPA was added and themixture was allowed to stand at room temperature for 5 days. The solventwas distilled off under reduced pressure, and the residue was purifiedby subjecting it to silica gel column chromatography (40 g, ethylacetate:hexane=1:1) to obtain 0.94 g of the title compound (yield: 70%).

mp 126-128° C.

IR (KBr) 2800, 1710, 1595, 1490, 1340, 1180, 780, 740, 700, 690, 540cm⁻¹.

Example 122 Methyl 4-[(3-benzhydryl-4-oxopiperidin-1-yl)methyl]benzoate

To 50 ml of dimethylformamide were added 5.25 g of3-benzhydryl-4-piperidinone hydrochloride, 4.2 g of methyl4-(bromomethyl)benzoate and 2.45 g of potassium carbonate and themixture was stirred at room temperature for 7 hours. The mixture wasextracted with 30 ml of ethyl acetate and the extract was washed withwater, and the ethyl acetate was distilled under reduced pressure. Theresidue was triturated with hexane and filtered to obtain 6.13 g of thetitle compound (yield: 85%).

mp 107-108° C.

IR (KBr) 2800, 1710, 1610, 1490, 1430, 1280, 1105, 760, 740, 700, 540cm⁻¹.

Example 123 4-[(3-Benzhydryl-4-oxopiperidin-1-yl)methyl]benzoic Acid

To a solution of 4.13 g of4-[(3-benzhydryl-4-oxopiperidin-1-yl)methyl]benzoic acid methyl ester in30 ml of methanol was added 20 ml of 1 N aqueous solution of sodiumhydroxide, and the mixture was stirred in an oil at 60° C. bath for 3hours. After cooling, 120 ml of 1 N hydrochloric acid was added theretoand a precipitate was collected by filtration. After dissolving inCH₂Cl₂/MeOH, the solution was purified by subjecting it to silica gelcolumn chromatography (150 g, ethyl acetate:hexane=1:1) to obtain 1.8 gof the title compound as foam (yield: 44%).

H-NMR (CDCl₃) δ: 2.30-2.95 (m, 6H), 3.42 (m, 1H), 3.50 and 3.64 (ABq,2H, J=13.5 Hz), 3.93 (s, 3H), 4.62 (d, 1H, J=11.2 Hz), 7.05-8.08 (m,14H).

To a solution of 0.81 g of the foam residue in 30 ml of ethyl ether wasadded 1 ml of a solution of 4 N HCl/dioxane. The precipitate wascollected by filtration to obtain 0.81 g of the hydrochloride of thetitle compound.

mp 179-181° C.

IR (KBr) 3025, 2550, 1720, 1490, 1450, 1415, 1370, 1205, 1180, 1105,750, 700, 540 cm⁻¹.

Example 124 1-Acetyl-3-[bis(4-methylphenyl)methyl]-4-piperidinone

According to the same manner as that described in Example 7, the titlecompound was obtained (yield: 22%).

mp 142-144° C.

IR (KBr) 2925, 1720, 1650, 1510, 1425, 1300, 1240, 1050, 985, 800, 760,540 cm⁻¹.

Example 125 3-[Bis(4-methylphenyl)methyl]-4-piperidinone

To 1-acetyl-3-[bis(4-methylphenyl)methyl]-4-piperidinone were added 30ml of water and 30 ml of conc. hydrochloric acid and the mixture wasstirred in an oil bath at 130° C. for 8 hours, and further at 90° C. foradditional 16 hours. The solvent was distilled off under reducedpressure, and the residue was triturated with ethanol and filtered.Washing with ethyl ether gave 3.6 g of the hydrochloride of the titlecompound (yield: 79%).

mp 209-210° C.

IR (KBr) 3050, 2700, 1725, 1510, 1425, 1130, 810, 755, 555 cm⁻¹.

Example 126 2-Oxo-2-phenylethyl[4-[(3-Benzhydryl-4-oxopiperidin-1-yl)methyl]phenyl]acetate

To 40 ml of dimethylformamide were added 4.3 g of3-benzhydryl-4-piperidinone hydrochloride, 5 g of 2-oxo-2-phenylethyl[4-(bromomethyl)phenyl]acetate and 2 g of potassium carbonate and themixture was stirred at room temperature for 2 hours. The mixture wasextracted with 30 ml of ethyl acetate and the extract was washed withwater, and the ethyl acetate was distilled off under reduced pressure.The residue was purified by subjecting it to silica gel columnchromatography (150 g, ethyl acetate:hexane=1:1) to obtain 7.1 g of thetitle compound as an oil (yield: 88%).

¹H-NMR (CDCl₃) δ: 2.30-2.90 (m, 6H), 3.36 (m, 1H), 3.47 and 3.59 (ABq,2H, J=13.6 Hz), 3.93 (s, 3H), 4.62 (d, 1H, J=11 Hz), 7.05-8.00 (m, 14H).

To a solution of 1 g of the oily title compound in 50 ml of ethyl etherwas added 1 ml of a solution of 4 N HCl/dioxane. The precipitate wascollected by filtration to obtain 0.81 g of the hydrochloride of thetitle compound.

mp 99-110° C.

IR (KBr) 3400, 1730, 1700, 1595, 1450, 1220, 1150, 970, 745, 700, 540cm⁻¹.

Example 127 [4-[(3-Benzhydryl-4-oxopiperidin-1-yl)methyl]phenyl]aceticAcid

To a solution of 5.9 g of 2-oxo-2-phenylethyl[4-[(3-benzhydryl-4-oxopiperidin-1-yl)methyl]phenyl]acetate in 20 ml oftetrahydrofuran was added 15 ml of 1 N aqueous solution of sodiumhydroxide under ice-cooling in ice. After stirring for 60 minutes, 15 mlof 1 N aqueous solution of sodium hydroxide was further added thereto.After allowing to stand at room temperature for 16 hours, 30 ml of 1 Nhydrochloric acid was added with stirring, and tetrahydrofuran wasdistilled off under reduced pressure. The gummy water-insoluble residuewas dissolved in CH₂Cl₂/MeOH, and then the solution was subjected tosilica gel column chromatography (150 g, ethyl acetate:hexane=1:1). Thedesired fraction was concentrated and ethyl ether was added thereto. Themixture was filtered and 2 ml of a solution of 4 N HCl/dioxane was addedto the filtrate. The precipitate was collected by filtration to obtain2.67 g of a hydrochloride of the title compound (yield: 57%).

mp 176-178° C.

IR (KBr) 2950, 2560, 1760, 1730, 1495, 1450, 1350, 1170, 780, 745, 700,540 cm⁻¹.

Example 128 4-[(3-Benzhydryl-4-oxopiperidin-1-yl)methyl]benzamide

To 10 ml of dimethylformamide were added 1 g of3-benzhydryl-4-piperidinone hydrochloride, 0.6 g of4-(bromomethyl)benzamide and 1.4 g of potassium carbonate and themixture was stirred at room temperature for 3 hours, and then at 100° C.for 20 minutes. The mixture was extracted with 30 ml of ethyl acetateand the extract was washed with water and ethyl acetate was distilledoff under reduced pressure. The residue was purified by subjecting it tosilica gel column chromatography (40 g, ethyl acetate) to obtain 1 g ofthe title compound as an oil.

¹H-NMR (CDCl₃) δ: 2.30-2.95 (m, 6H), 3.30-3.70 (m, 3H), 4.61 (m, 1H),7.00-7.78 (m, 14H).

To a solution of 1 g of the oily title compound in 10 ml of ethanol wasadded 1 ml of a solution of 4 N HCl/dioxane, and the solvent wasdistilled off under reduced pressure. To the residue was added ethylether and the mixture was stirred. The precipitate was collected byfiltration to obtain 1 g of the hydrochloride of the title compound(yield: 69%).

mp 133-134° C. (decomposition)

IR (KBr) 1730, 1660, 1615, 1565, 1490, 1450, 1420, 1380, 740, 700, 540cm⁻¹.

Example 1293-[Bis(4-methylphenyl)methyl]-1-(4-hydroxybenzyl)-4-piperidinone

To 15 ml of dichloromethane were added 1.1 g of3-[bis(4-methylphenyl)methyl]-4-piperidinone hydrochloride, 1.7 ml ofisopropylethylamine and 0.7 g of 4-hydroxybenzyl alcohol, the mixturewas stirred at room temperature and 1 ml of EPPA was added thereto.After stirring at room temperature for 15 minute, the solvent wasdistilled off under reduced pressure. The residue was purified bysubjecting it to silica gel column chromatography (40 g, ethylacetate:hexane=1:1) and recrystallized from ethyl ether to obtain 0.73 gof the title compound (yield: 46%).

mp 156-157° C.

IR (KBr) 3300, 2900, 1690, 1610, 1590, 1510, 1340, 1255, 1230, 1180,1100, 800, 775, 550, 540 cm⁻¹.

Example 130 4-Benzhydryl-1-(4-hydroxybenzyl)-3-piperidinone

To 15 ml of dichloromethane were added 1,1 g of4-benzhydryl-3-piperidinone hydrochloride, 1.7 ml of isopropylethylamineand 0.5 g of 4-hydroxybenzyl alcohol. After addition of 1 ml of EPPA,the mixture was stirred at room temperature for 15 minutes, the solventwas distilled off under reduced pressure and the residue was purified bysubjecting it to silica gel column chromatography (40 g, ethylacetate:hexane=1:1) to obtain the title compound as an oil.

¹H-NMR (CDCl₃) δ: 1.60-1.90 (m, 2H), 2.50, 2.85 (m, 2H), 2.89 and 3.13(ABq, 2H, J=13 Hz), 3.30 (m, 1H), 3.51 (s, 2H), 4.39 (d, 1H, J=9.8 Hz),6.73-7.28 (m, 14H)

The above oil was dissolved in ethyl acetate and 1 ml of a solution of4N HCl/dioxane was added thereto. The precipitate was collected byfiltration to obtain 1.2 g of the hydrochloride of the title compound(yield: 88%).

mp 187-188° C.

IR (KBr) 3150, 2550, 1730, 1610, 1590, 1515, 1490, 1450, 1370, 1270,1230, 1210, 1170, 740, 700 cm⁻¹.

Example 131 3-(5H-Dibenzo[a,d]cyclohepten-5-yl)-4-piperidinone

To a suspension of 6.3 g of3-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-benzyl-4-piperidinone in 100 ml ofmethanol was added 1.5 ml of conc. hydrochloric acid and the mixture wasstirred. Then, after addition of 3 g of 10% Pd—C, the mixture wasstirred for 6 hours under a hydrogen atmosphere. After filtration, thefiltrate was distilled under reduced pressure, and then the residue wasdissolved in a small amount of ethanol. Crystals precipitated werecollected by filtration to obtain 4.5 g of the hydrochloride of thetitle compound as a crystal (yield: 83%).

mp 182-183° C.

IR (KBr) 2900, 2430, 2375, 1720, 1490, 1450, 1445, 1400, 1185, 805, 770,755, 695 cm⁻¹.

Example 1323-(5H-Dibenzo[a,d]cyclohepten-5-yl)-1-(4-hydroxybenzyl)-4-piperidinone

To 15 ml of dichloromethane were added 1.1 g of3-(5H-dibenzo[a,d]cyclohepten-5-yl)-4-piperidinone hydrochloride, 1.7 mlof isopropylethylamine and 0.5 g of 4-hydroxybenzyl alcohol and themixture was stirred at room temperature. Then, 1 ml of EPPA was addedthereto and, after stirring at room temperature for 30 minutes, thesolvent was distilled off under reduced pressure. The residue waspurified by subjecting it to silica gel column chromatography (40 g,ethyl acetate:hexane=1:1) and recrystallized from ethyl ether to obtain0.56 g of the title compound (yield: 42%).

mp 156-157° C.

IR (KBr) 3020, 2820, 2790, 1700, 1490, 1450, 1335, 1235, 1180, 1110,805, 775, 760, 730, 695, 550, 460 cm⁻¹.

Example 133 3-(9H-Xanten-9-yl)-4-piperidinone

To a suspension of 6 g of 1-benzyl-3-(9H-xanten-9-yl)-4-piperidinone in100 ml of methanol was added 1.5 ml of conc. hydrochloride and themixture was stirred. After addition of 3 g of 10% palladium carbon, themixture was stirred under a hydrogen atmosphere for 6 hours. The mixturewas filtered, the filtrate was distilled off under reduced pressure, andthen the residue was dissolved in a small amount of ethanol. Crystalsprecipitated were collected by filtration to obtain 3.2 g of thehydrochloride of the title compound as crystals (yield: 63%).

mp 202-203° C.

IR (KBr) 2900, 2800, 2700, 1705, 1595, 1570, 1475, 1450, 1250, 900, 755,470, 455 cm⁻¹.

Example 134 1-(4-Hydroxybenzyl)-3-(9H-xanten-9-yl)-4-piperidinone

To 15 ml of dichloromethane were added 1.1 g of3-(9H-xanten-9-yl)-4-piperidinone hydrochloride, 1.7 ml ofisopropylethylamine and 0.5 g of 4-hydroxybenzyl alcohol and the mixturewas stirred at room temperature. Then, 1 ml of EPPA was added thereto,the mixture was stirring at room temperature for 30 minutes, and thesolvent was distilled off under reduced pressure. The residue waspurified by subjecting it to silica gel column chromatography (40 g,ethyl acetate:hexane=1:1) and recrystallized from ethyl ether to obtain1 g of the title compound (yield: 75%).

mp 171-172° C.

IR (KBr) 3350, 2810, 2760, 1700, 1615, 1590, 1515, 1450, 1340, 1240,1210, 1185, 1100, 1090, 760 cm⁻¹.

Example 1353-[Bis(4-fluorophenyl)methyl]-1-(2-methoxy-5-nitrobenzyl)-4-piperidinone

To a solution of 3 g of 3-[bis(4-fluorophenyl)methyl]-4-piperidinonehydrochloride and 2.46 g of 2-methoxy-5-nitrobenzyl bromide in 20 ml ofdimethylformamide was added 4.2 mg of potassium carbonate with stirringat room temperature. After stirring for 3 hours, 50 ml of ethyl acetateand 50 ml of brine were added thereto. The ethyl acetate layer wasseparated and washed with water, and the solvent was distilled off underreduced pressure. The residue was purified by subjecting it to silicagel column chromatography (11 g, ethyl acetate:hexane=1:1) to obtain thetitle compound as an oil.

¹H-NMR (CDCl₃) δ: 2.35-2.90 (m, 6H), 3.57 (s, 2H), 3.88 (s, 3H), 4.55(d, 1H, J=11 Hz), 6.80-7.28, 8.15-8.35 (m, 11H).

The above oil was dissolved in 30 ml of ethyl ether and 3 ml of asolution of 4 N HCl/dioxane was added thereto with stirring. Theprecipitate was collected by filtration to obtain 4.5 g of thehydrochloride of the title compound (yield: quantitative).

mp 166-167° C.

IR (KBr) 3425, 2950, 1730, 1590, 1505, 1340, 1275, 1220, 1155, 1095,1015, 830, 750, 635, 550 cm⁻¹.

Example 1361-(5-Amino-2-methoxybenzyl)-3-[bis(4-fluorophenyl)methyl]-4-piperidinone

To a mixture of 80 ml of methanol and 10 ml of water were added 2.8 g of3-[bis(4-fluorophenyl)methyl]-1-(2-methoxy-5-nitrobenzyl)-4-piperidinoneand 1.8 g of 5% Pd—C. The mixture was stirred at room temperature for 2hours under a hydrogen atmosphere. After confirming the absorption of acalculated amount of hydrogen, the reaction mixture was filtered, 1 mlof a solution of 4 N HCl/dioxane was added to the filtrate, and thesolvent was distilled off under reduced pressure. To the residue wasadded 30 ml of ethanol, and the ethanol was distilled off. The residuewas dissolved in ethyl acetate to precipitate crystals. The crystalswere collected by filtration to obtain 1.4 g of the dihydrochloride ofthe title compound (yield: 50%).

mp 200-203° C.

IR (KBr) 2800, 2550, 1730, 1600, 1505, 1450, 1270, 1220, 1160, 840, 555cm⁻¹.

The above hydrochloride was added to a mixture of chloroform and water,and the mixture was neutralized with sodium bicarbonate. The solvent wasdistilled off under reduced pressure to obtain the title compound.

¹H-NMR (CDCl₃) δ: 2.35-2.95 (m, 6H), 3.29 (m, 1H), 3.49 (s, 2H), 3.70(s, 3H), 4.58 (d, 1H, J=11 Hz), 6.55-7.27 (m, 1H).

Example 137 4-Benzhydryl-1-benzyl-3-pyrrolidinone

To a solution of 1.75 g of 1-benzyl-3-pyrrolidinone in 15 ml ofdichloromethane were added 4 ml of TMSOTf and then 1.84 g of benzhydrolwith stirring under ice-cooling. After stirring at room temperature for16 hours, ice water was added to the mixture and the mixture wasneutralized with sodium bicarbonate. The dichloromethane layer wasseparated, and the solvent was distilled off under reduced pressure. Theresidue was purified by subjecting it to silica gel columnchromatography (40 g, ethyl acetate hexane=1:4) to obtain the titlecompound as an oil.

¹H-NMR (CDCl₃) δ: 2.47-2.68, 3.15-3.50 (each m, 5H), 3.49 and 3.70 (ABq,2H, J=13 Hz), 4.50 (d, 1H, J=7 Hz), 7.00-7.36 (m, 15H).

The above oil was dissolved in ethyl ether, and 1 ml of a solution of 4N HCl/dioxane was added thereto with stirring. The precipitate wascollected by filtration to obtain 0.84 g of the hydrochloride of thetitle compound as a powder (yield: 22%).

IR (KBr) 3400, 3025, 2350, 1760, 1595, 1490, 1450, 1170, 1025, 745, 695cm⁻¹.

Example 138 1-Benzyl-4-[bis(4-fluorophenyl)methyl]-3-pyrrolidinone

According to the same manner as that described in Example 137, the titlecompound was obtained as an oil.

¹H-NMR (CDCl₃) δ: 2.43-2.69, 3.15-3.32 (each m, 5H), 3.50 and 3.70 (ABq,2H, J=13 Hz), 4.45 (d, 1H, J=6.9 Hz), 6.89-7.35 (m, 13H).

The title compound was dissolved in ethyl ether and a calculated amountof a solution of 4 N HCl/dioxane was added thereto, and then the solventwas distilled off under reduced pressure. Hexane was added to theresidue, and the resultant powder was collected by filtration to obtain1 g of the hydrochloride of the title compound (yield: 24%).

IR (KBr) 3400, 2925, 2360, 1760, 1600, 1505, 1455, 1415, 1225, 1155,1010, 825, 750, 700, 565, 545, 520 cm⁻¹.

Example 139 4-[Bis(4-fluorophenyl)methyl]-3-pyrrolidinone

To 150 ml of methanol were added 7.5 g of1-benzyl-4-[bis(4-fluorophenyl)methyl]-3-pyrrolidinone, 3 g of 10% Pd—Cand 2 ml of conc. hydrochloric acid. After stirring for 5 hours under ahydrogen atmosphere, the reaction mixture was filtered and the filtratewas distilled off under reduced pressure. After dissolving in a smallamount of ethanol, crystals precipitated were collected by filtration toobtain 4 g of the hydrochloride of the title compound (yield: 63%).

mp 180-181° C.

IR (KBr) 2875, 2730, 1760, 1600, 1510, 1415, 1230, 1015, 875, 835, 610,575, 545 cm⁻¹.

To the hydrochloride of the title compound were added chloroform andwater and the mixture was neutralized with sodium bicarbonate. Afterseparation of the chloroform layer, the solvent was distilled off toobtain the title compound.

¹H-NMR (CDCl₃) δ: 2.95-3.60 (each m, 5H), 4.49 (d, 1H, J=5.6 Hz),6.90-7.27 (m, 8H).

Example 1404-[Bis(4-fluoropheny)methyl]-1-(4-hydroxybenzyl)-3-pyrrolidinone

To 15 ml of dichloromethane were added 1 g of4-[bis(4-fluorophenyl)methyl]-3-pyrrolidinone hydrochloride, 1.7 ml ofisopropylethylamine and 0.5 g of 4-hydroxybenzyl alcohol. Then, 1 ml ofEPPA was added thereto, the mixture was stirred at room temperature for15 minutes, the solvent was distilled off under reduced pressure. Theresidue was purified by subjecting it to silica gel columnchromatography (40 g, ethyl acetate:hexane=1:1) to obtain the titlecompound was obtained as an oil.

¹H-NMR (CDCl₃) δ: 2.35-2.70, 3.14-3.35 (each m, 5H), 3.44 and 3.62 (ABq,2H, J=12.8 Hz), 4.44 (d, 1H, J=6.6 Hz), 6.75-7.30 (m, 12H).

The above oil was dissolved in 70 ml of ethyl ether and 2 ml of asolution of 4 N HCl/dioxane was added thereto. The precipitate wascollected by filtration to obtain 1.2 g of the hydrochloride of thetitle compound (yield: 84%).

mp 126-127° C.

IR (KBr) 3200, 2950, 2550, 1770, 1610, 1505, 1445, 1415, 1270, 1230,1175, 1160, 1010, 835, 560, 550, 520 cm⁻¹.

Example 1414-[Bis(4-fluorophenyl)methyl]-1-(2-methoxybenzyl)-3-pyrrolidinone

To 15 ml of dichloromethane were added 0.8 g of4-[bis(4-fluorophenyl)methyl]-3-pyrrolidinone hydrochloride, 1.7 ml ofisopropylethylamine and 0.5 g of 2-methoxybenzyl alcohol. Then, 1 ml ofEPPA was added thereto, the mixture was allowed to stand at roomtemperature for 48 hours, and the solvent was distilled off underreduced pressure. The residue was purified by subjecting it to silicagel column chromatography (40 g, ethyl acetate:hexane=1:2) to obtain thetitle compound as an oil.

¹H-NMR (CDCl₃) δ: 2.40-2.74, 3.20-3.35 (each m, 5H), 3.60 and 3.71 (ABq,2H, J=13 Hz), 3.79 (s, 3H), 4.42 (d, 1H, J=6.9 Hz), 6.84-7.29 (m, 12H).

The above oil was dissolved in 50 ml of ethyl ether, 1 ml of a solutionof 4 N HCl/dioxane was added thereto, and the solvent was distilled offunder reduced pressure. Hexane was added and the precipitate wascollected by filtration to obtain 1.2 g of the hydrochloride of thetitle compound (yield: 84%).

IR (KBr) 3400, 2950, 2500, 1760, 1660, 1510, 1460, 1250, 1220, 1155,1120, 1020, 830, 755, 565 cm⁻¹.

Example 142 3-(Diphenylmethylene)-1-methyl-4-piperidinone

To a solution of 1.1 g of 1-methyl-4-piperidinone in 10 ml ofdichloromethane were added 2 ml of TMSOTf, 2.4 g ofdichlorodiphenylmethane and then 2 g of zinc bromide with stirring underice-cooling. After stirring at room temperature for 16 hours, ice waterwas added thereto and the mixture was neutralized with sodiumbicarbonate.

The dichloromethane layer was dried over anhydrous magnesium sulfate,and then the solvent was distilled off under reduced pressure. Theresidue was purified by subjecting it to silica gel columnchromatography (100 g, ethyl acetate). The solvent was distilled off,and the residue (crystal) was triturated with a small amount of ethylether and filtered to obtain 0.38 g of the title compound (yield: 14%).

mp 129-131° C.

IR (KBr) 3660, 2950, 2840, 2790, 2760, 1690, 1605, 1590, 1490, 1440,1260, 1230, 1170, 1035, 930, 770, 700, 630, 545, 420 cm⁻¹.

Example 143 1-Benzyl-3-(diphenylmethylene)-4-piperidinone

To a solution of 1.9 g of 1-benzyl-4-piperidinone in 10 ml ofdichloromethane were added 4 ml of TMSOTf, 2.4 g ofdichlorodiphenylmethane and then 1 g of zinc bromide with stirring underice-cooling. After stirring at room temperature for 16 hours, ice waterwas added thereto and the mixture was neutralized with sodiumbicarbonate. The dichloromethane layer was dried over anhydrousmagnesium sulfate, and then the solvent was distilled off under reducedpressure. The residue was purified by subjecting it to silica gel columnchromatography (100 g, ethyl acetate:hexane=1:1). The solvent wasdistilled off, and the residue (crystal) was triturated with a smallamount of ethyl ether and filtered to obtain 0.35 g of the titlecompound (yield: 6.6%).

mp 135-137° C.

IR (KBr) 3030, 2810, 2750, 1740, 1695, 1600, 1495, 1450, 1445, 1315,1250, 1200, 1125, 780, 705, 550 cm⁻¹.

Example 1443-Benzhydryl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-piperidinone

To a solution of 0.30 g of 3-benzhydryl-4-piperidinone hydrochloride,0.31 g of 3,5-bis(trifluoromethyl)benzoic acid, 0.20 g of1-hydroxy-1H-benzotriazole-monohydrate and 0.11 g of triethylamine in 5ml of dimethylformamide was added 0.38 g of1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, and themixture was stirred at room temperature for 14 hours. After extractedwith 50 ml of ethyl acetate, the extract was washed with an aqueoussolution of sodium hydrogen carbonate and then water, and dried overmagnesium sulfate. The solvent was distilled off under reduced pressure.The residue was purified by subjecting it to silica gel chromatography(6 g, ethyl acetate:hexane=1:4). The residue (amorphous) was collectedby filtration with hexane to obtain 0.47 g of the title compound (yield:92%).

¹H-NMR (CDCl₃) δ: 2.40-2.70 (2H, m), 3.20-3.80 (4H, m), 4.10-4.60 (2H,m), 6.80-8.00 (13H, m).

Example 1453-[Bis(4-chlorophenyl)methyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-4-piperidinone

According to the same manner as that described in Example 144, 0.37 g ofthe title compound was obtained (yield: 64%).

¹H-NMR (CDCl₃) δ: 2.40-2.80 (2H, m), 3.00-3.35 (2H, m), 3.35-3.60 (2H,m), 3.80-4.80 (2H, m), 6.60-7.40 (8H, m), 7.70-8.05 (3H, m).

Example 1463-[Bis(4-fluorophenyl)methyl]-1-ethoxycarbonyl-4-piperidinone

A 200 ml-volume three-necked flask was charged with 5.0 g (29.2 mmol) of1-ethoxycarbonyl-4-piperidinone and 20 ml of dichloromethane, and asolution of 11.6 ml (64.3 mmol) of trimethyl silyltriflate (TMSOTf) in10 ml of dichloromethane was added dropwise thereto with stirring underice-cooling at 5° C. or below. Then, to the mixture was added 5.2 g(23.4 mmol) of 4,4′-difluorobenzhydrol with stirring at the sametemperature. The cooling bath was removed, the mixture was allowed tostand at room temperature overnight, and then 30 ml of water was addedthereto with stirring under ice-cooling. The organic phase wasseparated. The aqueous layer was extracted with 30 ml of dichloromethaneand combined with the above organic layer, followed by washing with 30ml of water. The combined organic layer was concentrated under reducedpressure, 30 ml of ether was added to the residue, and the mixture wasstirred under ice-cooling. The precipitated crystals were collected byfiltration, washed with ether and dried under reduced pressure to obtain6.4 g of the title compound as crystals (yield: 73%).

Elemental analysis: C₂₁H₂₁F₂NO₃:

Calculated: C, 67.55; H, 5.67; N, 3.75.

Found: C, 67.46; H, 5.61; N, 3.77.

¹H-NMR (CDCl₃) δ: 1.19-1.25 (m, 2H), 3.32 (m, 2H), 3.50-4.00 (m, 3H),4.16-4.20 (m, 2H), 4.34 (d, 1H, J=10.4 Hz), 4.35 (s, 1H), 6.93-7.01 (m,4H), 7.18-7.25 (m, 4H).

Example 147 3-[(2-Fluorophenyl)(phenyl)methyl]-4-piperidinone

To 2.0 g (4.88 mmol) of1-benzyl-3-[(2-fluorophenyl)(phenyl)methyl]-4-piperidinone hydrochloridewere added 50 ml of methanol and 5 ml of water and the mixture wasdissolved with warming. After purged with nitrogen, 0.5 g of 10% Pd—C(wet) was added thereto and the mixture was cooled to room temperature.Then, in a hydrogen stream, the mixture was stirred at atmosphericpressure for 7 hours. The mixture was filtered through Celite, washedwith 5 ml of methanol, and the filtrate was concentrated. The mixturewas allowed to stand in a refrigerator and then precipitated crystalswere collected by filtration, dried to obtain 1.24 g of thehydrochloride of the title compound (yield: 79%).

mp 204-205° C.

¹H-NMR (CDCl₃) δ: 2.61-3.70 (m, 6H), 6.28 (m, 1H), 4.72 (d, 0.5H, J=11.0Hz), 4.78 (d, 0.5H, J=10.4 Hz), 6.95-7.37 (m, 9H).

IR (KBr): 3441, 2900, 2778, 2699, 2637, 2511, 2465, 1720, 1589, 1490,1454, 1382, 1226, 757, 742, 699, 519 cm⁻¹.

Elemental analysis: C₁₈H₁₈FNO.HCl:

Calculated: C, 67.60; H, 5.99.

Found: C, 66.99; H, 5.86.

Example 1483-[Bis(4-fluorophenyl)methyl]-1-[(2-methoxy-1-naphthyl)methyl]-4-piperidinone

A 25 ml round-bottomed flask was charged with 1.0 g (2.96 mmol) of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 613 mg (3.26mmol) of 2-methoxy-1-naphthalenemethanol, 2.18 g (16.87 mmol) ofdiisopropylethylamine, 10 ml of dichloromethane and 889 mg (4.44 mmol)of EPPA and the mixture was stirred at room temperature for 2 days. Tothe reaction mixture was added 10 ml of water and shaken. Thedichloromethane layer was separated, and the aqueous layer was extractedonce again with 10 ml of dichloromethane. The organic layers werecombined and washed with water (10 ml) and then saturated brine (10 ml).The mixture was dried over an anhydrous magnesium sulfate andconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (50 g, n-hexane-ethyl acetate 4:1, V/V)to obtain 644 mg of the title compound as crystals (yield: 46%).

mp 125-126° C.

Elemental analysis: C₃₀H₂₇F₂NO₂

Calculated: C, 76.41; H, 5.77; N, 2.97.

Found: C, 76.21; H, 5.82; N, 2.79.

IR (KBr): 2948, 2844, 2786, 1708, 1625, 1598, 1504, 1471, 1415, 1340,1297, 1250, 1191, 1157, 1104, 1085, 1068, 1057, 1024, 953, 854, 824cm⁻¹.

Example 1493-[Bis(4-fluorophenyl)methyl]-1-[(3-hydroxy-6-methyl-2-pyridinyl)methyl]-4-piperidinone

A 25 ml round-bottomed flask was charged with 1.0 g (2.96 mmol) of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 453 mg (3.26mmol) of 2,6-lutidine-α²-3-diol, 2.18 g (16.87 mmol) ofdiisopropylethylamine, 10 ml of dichloromethane and 889 mg (4.44 mmol)of EPPA and the mixture was stirred at room temperature for 6 days. Tothe reaction mixture was added 10 ml of water and shaken. Thedichloromethane layer was separated, and the aqueous layer was extractedonce again with 10 ml of dichloromethane. The organic layers werecombined and washed with water (10 ml) and saturated brine (10 ml). Themixture was dried over an anhydrous magnesium sulfate and concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (50 g, n-hexane-ethyl acetate 1:1, V/V) to obtain537 mg of the title compound (yield: 43%).

Elemental analysis: C₂₅H₂₄F₂N₂O₂

Calculated: C, 71.07; H, 5.73; N, 6.63.

Found: C, 70.92; H, 5.74; N, 6.69.

IR (KBr): 3433, 1721, 1604, 1509, 1468, 1272, 1226, 1160, 829, 733, 556cm⁻¹.

Example 1503-[Bis(4-fluorophenyl)methyl]-1-[(2,6-dimethoxy-3-pyridinyl)methyl]-4-piperidinone

(Step 1)

A 200 ml round-bottomed flask was charged with 5.0 g (27.3 mmol) of2,6-dimethoxynicotinic acid, 100 ml of ethanol and 5.4 g (54.6 mmol) ofsulfuric acid, and the mixture was heated under reflux for 2 days. Afterconcentration under reduced pressure, to the residue were added 100 mlof ethyl acetate and 50 ml of water, the mixture was shaken, and theorganic layer was separated. The aqueous layer was neutralized and thenextracted once again with ethyl acetate. The ethyl acetate layers werecombined, and washed with 100 ml of water and 100 ml of saturated brine.The mixture was dried over magnesium sulfate and concentrated underreduced pressure to obtain 2,6-dimethoxynicotinic acid ethyl ester. Thiswas dissolved in 50 ml of toluene and 10.26 g (35.5 mmol) ofNaAlH₂(OCH₂CH₂OMe)₂ was added thereto. Then, the mixture was stirredunder ice-cooling for 1 hour and then at room temperature for 7 hours.To the reaction mixture were added 50 ml of 10% Rochelle salt and 50 mlof ethyl acetate, and the organic layer was separated. The aqueous layerwas extracted once again with ethyl acetate and the ethyl acetate layerswere combined and washed with 50 ml of water and 50 ml of saturatedbrine. The mixture was dried over magnesium sulfate and concentratedunder reduced pressure to obtain 2,6-dimethoxy-3-pyridylmethanol.

(Step 2)

A 25 ml round-bottomed flask was charged with 1.0 g (2.96 mmol) of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 551 mg (3.26mmol) of 2,6-dimethoxy-3-pyridylmethanol, 2.18 g (16.87 mmol) ofdiisopropylethylamine, 10 ml of dichloromethane, and 889 mg (4.44 mmol)of EPPA and the mixture was stirred at room temperature for about 3days. To the reaction mixture was added 10 ml of water, the mixture wasshaken and the dichloromethane layer was separated. The aqueous layerwas extracted once again with 10 ml of dichloromethane, and the organiclayers were combined and washed with water (10 ml), followed by asaturated brine (10 ml). The mixture was dried over an anhydrousmagnesium sulfate, concentrated under reduced pressure, and the residuewas purified by silica gel column chromatography (50 g, n-hexane-ethylacetate 4:1, V/V) to obtain 550 mg of the title compound (yield: 41%).

IR (KBr): 2949, 2803, 1718, 1605, 1589, 1506, 1482, 1421, 1389, 1318,1225, 1159, 1105, 1074, 1022, 955, 826, 806, 735, 578, 546 cm⁻¹.

Example 1513-Benzhydryl-1-[(2,6-dimethoxy-3-pyridinyl)methyl]-4-piperidinone

A 25 ml round-bottomed flask was charged with 1.0 g (3.64 mmol) of3-benzhydryl-4-piperidinone hydrochloride, 617 mg (3.64 mmol) of2,6-dimethoxy-3-pyridylmethanol, 2.44 g (18.89 mmol) ofdiisopropylethylamine, 10 ml of dichloromethane, and 995 mg (4.97 mmol)of EPPA and the mixture was stirred at room temperature for about 5days. To the reaction mixture was added 10 ml of water, the mixture wasshaken and the dichloromethane layer was separated. The aqueous layerwas extracted once again with 10 ml of dichloromethane, and the organiclayers were combined and washed with water (10 ml) followed by asaturated brine (10 ml). The mixture was dried over an anhydrousmagnesium sulfate, concentrated under reduced pressure, and the residuewas purified by silica gel column chromatography (50 g, n-hexane-ethylacetate 4:1, V/V) to obtain 806 mg of the title compound (yield: 58%).

IR (KBr): 3443, 2947, 1718, 1604, 1588, 1481, 1453, 1421, 1389, 1317,1249, 1209, 1102, 1022, 807, 748, 704, 547 cm⁻¹.

Example 1523-Benzhydryl-1-[[3,5-(bistrifluoromethyl)phenyl]acetyl]-4-piperidinone

A solution of 3.0 g (10 mmol) of 3-benzhydryl-4-piperidinonehydrochloride, 1 g (10 mmol) of triethylamine, 2.99 g (11 mmol) of3,5-(bistrifluoromethyl)phenylacetic acid, 3.26 g (17 mmol) of WSC, 610mg (5 mmol) of DMAP, and 13 ml of DMF was stirred at room temperaturefor 4.5 hours. To the reaction mixture was added 150 ml of water, 100 mlof ethyl acetate and 30 ml of hexane, and the mixture was shaken andthen separated into layers. The organic layer was washed with 0.3 Nhydrochloric acid (30 ml×2) and an aqueous sodium bicarbonate, dried andconcentrated under reduced pressure. The crystalline residue was washedwith isopropyl ether and dried to obtain 4.59 g of the title compound ascrystals (yield: 88%).

mp 124-124.5° C.

Elemental analysis: C₂₈H₂₃F₆NO₂

Calculated: C, 64.74; H, 4.46; N, 2.70.

Found: C, 64.75; H, 4.55; N, 2.60.

¹H-NMR (CDCl₃) δ: 2.42-4.37 (m, 10H), 7.17-7.83 (m, 13H).

Example 1533-Benzhydryl-1-[(2-methoxy-4-methylphenyl)sulfonyl]-4-piperidinone

A suspension of 604 mg (2 mmol) of 3-benzhydryl-4-piperidinonehydrochloride in 4 ml of dichloromethane was dissolved by addition of323 mg (2.5 mmol) of isopropylethylamine. Then, 122 mg (1 mmol) of DMAPand 663 mg (3 mmol) of 2-methoxy-4-methylbenzensulfonyl chloride wereadded thereto and the mixture was stirred at room temperature for 1.5hours. To the reaction mixture were added 20 ml of ethyl acetate, 20 mlof diisopropyl ether and 20 ml of water, the mixture was shaken andseparated into layers. The organic layer was washed with an aqueoussodium bicarbonate, dried and concentrated under reduced pressure. Thecrystalline residue was washed with diisopropyl ether and dried toobtain 820 mg of the title compound as crystals (yield: 91%).

mp 130-131° C.

Elemental analysis: C₂₆H₂₇NO₄.0.1H₂O (451.364)

Calculated: C, 69.19; H, 6.07; N, 3.10.

Found: C, 69.11; H, 6.10; N, 3.00.

¹H-NMR (CDCl₃)δ: 2.39 (s, 3H), 2.41-2.58 (m, 2H), 3.16-3.21 (m, 1H),3.43-3.48 (m, 1H), 3.57 (br, 1H), 3.79 (s, 3H), 4.49 (d, 1H), 6.78 (s,1H), 7.13-7.30 (m, 10H), 7, 69 (d, 1H).

Example 1543-Benzhydryl-1-[[2-(methylthio)-3-pyridinyl]carbonyl]-4-piperidinone

To 604 mg (2.0 mmol) of 3-benzhydryl-4-piperidinone hydrochloride wasadded with 6 ml of dichloromethane, and then 774 mg (6.0 mmol) ofdiisopropylethylamine was added to the mixture with stirring at roomtemperature. After dissolution, 122 mg (6.0 mmol) of DMAP and 774 mg (6mmol) of 2-methylthionicotinic acid chloride were added thereto and themixture was stirred for 2 hours. To the reaction mixture were added 20ml of isopropyl ether, 20 ml of ethyl acetate and 20 ml of water, themixture was shaken, and then the organic layer was separated. Theorganic layer was washed successively with aqueous sodium bicarbonate,dilute hydrochloric acid, aqueous sodium bicarbonate and water. Afterdrying over magnesium sulfate, the layer was concentrated under reducedpressure to obtain 0.83 g of the title compound as a pale yellow solid(quantitative).

¹H-NMR (CDCl₃) δ: 2.53-4.75 (m, 11H), 6.87-7.45 (m, 12H), 8.44, 8.52 (m,1H).

Elemental analysis: C₂₅H₂₄N₂O₂.0.2AcOEt

Calculated: C, 71.37; H, 5.94; N, 6.45.

Found: C, 71.28; H, 5.91; N, 6.57.

Example 155 3-Benzhydryl-1-[(3-methoxy-2-naphtyl)methyl]-4-piperidinone

(Step 1)

A 50 ml round-bottomed flask was charged with 2.3 g (10.6 mmol) of3-methoxy-2-naphthalenecarboxylic acid methyl ester and 18 ml oftoluene, and to the mixture was added 4.61 g (16 mmol) ofNaAlH₂(OCH₂CH₂OMe)₂ with stirring under ice-cooling. The mixture wasfurther stirred for about 2 hours under ice-cooling and then for 1 hourat room temperature. To the reaction mixture were added 20 ml of ethylacetate and 20 ml of a 10% aqueous solution of Rochelle salt, themixture was shaken and the organic layer was separated. The aqueouslayer was extracted once again with 20 ml of ethyl acetate, and theorganic layers were combined and washed twice with 20 ml of water andthen twice with 20 ml of a brine. The organic layer was filtered throughCelite, dried over MgSO₄ (anhydrous), concentrated under reducedpressure to obtain 1.47 g of 3-methoxy-2-naphthylmethanol (yield: 73%).

¹H-NMR (CDCl₃) δ: 3.96 (s, 3H), 4.82 (s, 2H), 7.12 (s, 1H), 7.19-7.51(m, 2H), 7.72-7.80 (m, 3H).

(Step 2)

A 25 ml round-bottomed flask was charged with 700 mg (3.72 mmol) of3-methoxy-2-naphthylmethanol, 1.12 g (3.72 mmol) of3-benzhydryl-4-piperidinone hydrochloride, 2.74 g (21.2 mmol) ofdiisopropylethylamine and 4 ml of dichloromethane, and an EPPA 1.12 g(5.58 mmol)/dichloromethane 2 ml solution was added thereto withstirring and then the mixture was stirred at room temperature for 2days. To the reaction mixture were added 20 ml of dichloromethane and 20ml of an aqueous sodium bicarbonate, the mixture was shaken, and thendichloromethane layer was separated. The aqueous layer was extractedagain with 20 ml of dichloromethane, and then the organic layers werecombined, and then washed successively with 20 ml of a saturated aqueoussodium bicarbonate, 20 ml of water and 20 ml of saturated brine. Afterdrying over anhydrous magnesium sulfate followed by concentration underreduced pressure, the residue was subjected to silica gel columnchromatography (50 g, n-hexane-ethyl acetate 5:1, V/V) to obtain 0.31 gof the title compound (yield: 19%).

¹H-NMR (CDCl₃) δ: 2.40-2.42 (m, 1H), 2.47-2.56 (m, 2H), 2.69-2.72 (m,1H), 2.80-2.82 (m, 1H), 3.40-3.43 (m, 1H), 3.69 (m, 2H), 3.84 (m, 3H),4.59 (d, 1H, J=10.8 Hz), 6.98-7.03 (m, 3H), 7.10-7.13 (m, 4H), 7.18-7.23(m, 2H), 7.28-7.36 (m, 3H), 7.40-7.44 (m, 1H), 7.70-7.75 (m, 3H).

Elemental analysis: C₃₀H₂₉NO₂.0.2H₂O

Calculated: C, 82.05; H, 6.75; N, 3.19.

Found: C, 82.12; H, 6.81; N, 3.07.

IR (KBr): 3026, 2951, 2795, 1716, 1633, 1599, 1494, 1473, 1451, 1432,1398, 1344, 1245, 1194, 1157, 1089, 1016, 898, 862, 830, 783, 745, 702,622, 545, 477 cm⁻¹.

Example 1563-Benzhydryl-1-[(3-methoxy-1-benzothien-2-yl)methyl]-4-piperidinone

To 604 mg (2.0 mmol) of 3-benzhydryl-4-piperidinone hydrochloride wasadded 5 ml of dichloromethane, and to the mixture was added 1.3 g (10mmol) of diisopropylethylamine with stirring at room temperature. Afterdissolution, 388 mg (2.0 mmol) of (3-methoxy-1-benzothien-2-yl)methanoland 800 mg (4 mmol) of EPPA were added thereto, and the mixture wasstirred for 40 hours. To the reaction mixture were added 40 ml ofisopropyl ether, 40 ml of ethyl acetate and 30 ml of water, the mixturewas shaken, and the organic layer was separated. The organic layer wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure, and the residue was subjected to silica gel columnchromatography (40 g, n-hexane-ethyl acetate 4:1, V/V) to obtain 200 mgof the title compound (yield: 23%).

¹H-NMR (CDCl₃) δ: 2.31-4.37 (m, 1H), 2.53-2.73 (m, 4H), 2.94-2.99 (m,1H), 3.37-3.40 (m, 1H), 3.73 (d, 1H), 3.79 (d, 1H), 3.84 (s, 3H), 4.67(d, 1H), 7.00-7.15 (m, 4H), 7.22-7.26 (m, 4H), 7.33-7.38 (m, 4H), 7.67(d, 1H), 7.77 (d, 1H).

Elemental analysis: C₂₈H₂₇NO₂S

Calculated: C, 76.16; H, 6.16; N, 3.17.

Found: C, 76.05; H, 6.13; N, 3.17.

Example 157 1-Benzyl-3-[(2-fluorophenyl)(phenyl)methyl]-4-piperidinone

(Step 1)

To a solution of 2.0 g (10 mmol) of 2-fluorobenzophenone in 20 ml ofmethanol was added 0.50 g of sodium borohydride with stirring underice-cooling, and the mixture was stirred for 2 hours at room temperatureuntil effervescence ceased. Then, methanol was distilled off underreduced pressure and 15 ml of 1 N HCl was added thereto. The mixture wasextracted twice with 25 ml of toluene. The organic layer was washed withwater, and concentrated under reduced pressure. For dehydration, theresidue was dissolved in 25 ml of toluene and the solution wasreconcentrated to obtain 1.75 g of 2-fluorobenzhydrol (yield: 87%).

(Step 2)

To a solution of 1.89 g (10.0 mmol) of 1-benzyl-4-piperidinone in 20 mlof dichloromethane was added dropwise 4.07 ml (22.5 mmol) oftrimethylsilyl triflate (TMSOTf) with stirring under ice-cooling at atemperature of 10° C. or below. After 10 minutes, a solution of 1.75 g(8.65 mmol) of 2-fluorobenzhydrol in 3 ml of dichloromethane was addedthereto. After stirring for 1 hour at room temperature, an aqueoussolution of sodium carbonate (Na₂CO₃ 2 g/H₂O 20 ml) was added dropwiseunder ice-cooling. The organic layer was separated, and the aqueouslayer was extracted once again with 20 ml of ethyl acetate, and theorganic layers were combined and dried over anhydrous magnesium sulfate.The mixture was concentrated under reduced pressure and the residue wassubjected to silica gel column chromatography (50 g, n-hexane-ethylacetate 6:1-3:1, V/V) to obtain the title compound. Then, this wasdissolved in a solution of 1 ml of conc. hydrochloric acid diluted with10 ml of ethanol and allowed to stand in a refrigerator overnight. Then,the precipitated crystals were collected by filtration, washed with 20ml of ethanol and dried under reduced pressure to obtain 2.53 g of thehydrochloride of the title compound (yield: 71%).

mp 214-215° C.

¹H-NMR (CDCl₃) δ: 2.41-3.04 (m, 3H), 3.42-3.66 (m, 3H), 3.92-4.06 (m,1H), 4.24-4.31 (m, 1H), 4.56 (d, 0.5H, J=10.2 Hz), 4.68 (d, 0.5H, J=11.4Hz), 4.85-5.02 (m, 1H), 6.91-7.53 (m, 14H).

IR (KBr): 3436, 2911, 2380, 1728, 1491 cm⁻¹.

Elemental analysis: C₂₅H₂₄FNO.HCl

Calculated: C, 73.25; H, 6.15.

Found: C, 73.10; H, 5.93.

Example 1581-Benzyl-3-[(2-chlorophenyl)(4-chlorophenyl)methyl]-4-piperidinone

According to the same manner as that described in Step 2 of Example 157,the hydrochloride of the title compound was obtained from2,4′-dichlorobenzhydrol and trimethylsilyl triflate.

mp 190-191° C.

¹H-NMR (CDCl₃) δ: 2.42-4.05 (m, 7H), 4.23-4.31 (m, 1H), 4.24-4.31 (m,1H), 4.68 (d, J=10.6 Hz), 4.93-5.06 (m, 1H), 7.07-7.55 (m, 13H).

IR (KBr): 3442, 3063, 2908, 2459, 2383, 1732, 1492, 1425, 1438, 1444,1411, 1368, 1341, 1089, 1036, 1014, 755, 700, 549, 522 cm⁻¹.

Elemental analysis: C₂₅H₂₃Cl₂NO.HCl.0.5 EtOH

Calculated: C, 64.54; H, 5.62.

Found: C, 64.54; H, 5.46.

Example 1593-[Bis(4-fluorophenyl)methyl]-1-(3,5-di-tert-butyl-2-methoxybenzyl)-4-piperidinone

(Step 1)

A 100 ml four-necked flask was charged with 5.0 g (20.1 mmol) of3,5-di-tert-butyl-2-methoxybenzyl aldehyde and 100 ml of ethanol. Then,762 mg (20.1 mmol) of sodium borohydride was added thereto with stirringunder ice-cooling and the mixture was stirred for 1 hour and allowed tostand at room temperature overnight. After concentrating under reducedpressure, to the residue were added 100 ml of ethyl acetate and 100 mlof water, the mixture was shaken, and then the organic layer wasseparated. The aqueous layer was extracted with 100 ml of ethyl acetate,and combined with the above organic layer. The mixture was washed with100 ml of water followed by 100 ml of saturated brine. After drying overanhydrous magnesium sulfate, the mixture was concentrated under reducedpressure, and the residue was recrystallized from ether to obtain 2.0 gof 3,5-di-tert-butyl-2-methoxybenzyl alcohol (yield: 40%).

¹H-NMR (CDCl₃) δ: 1.31 (s, 9H), 1.40 (s, 9H), 3.82 (s, 3H), 4.77 (d, 1H,J=5.2 Hz), 7.26 (d, 1H, J=2.4 Hz), 7.30 (d, 1H, J=2.8 Hz).

(Step 2)

A 25 ml round-bottomed flask was charged with 1.0 g (2.96 mmol) of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 0.82 g (3.26mmol) of 3,5-di-tert-butyl-2-methoxybenzyl alcohol, 2.18 g (16.87 mmol)of diisopropylethylamine, 10 ml of dichloromethane, and 889 mg (4.44mmol) of EPPA, and the mixture was stirred at room temperature for about3 days. To the reaction mixture was added 10 ml of water, the mixturewas shaken and then the dichloromethane layer was separated. The aqueouslayer was extracted with 10 ml of dichloromethane, and then the organiclayers were combined and washed with water (10 ml) followed by asaturated brine (10 ml). After drying over anhydrous magnesium sulfate,the mixture was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (50 g, n-hexane-ethylacetate 4:1, V/V) to obtain 854 mg of the title compound (yield: 54%).

Elemental analysis: C₃₄H₄₁ F₂NO₂

Calculated: C, 76.52; H, 7.74; N, 2.62.

Found: C, 76.44; H, 7.79; N, 2.49.

IR (KBr): 3421, 2962, 2868, 2800, 1719, 1604, 1508, 1478, 1429, 1392,1362, 1346, 1301, 1274, 1229, 1158, 1102, 1074, 1013, 904, 884, 825,795, 768, 751, 653, 579, 550 cm⁻¹.

Example 1603-[Bis(4-fluorophenyl)methyl]-1-(2,5-dimethoxybenzyl)-4-piperidinone

(Step 1)

A 100 ml four-necked flask was charged with 5.0 g (30.1 mmol) of2,5-dimethoxybenzaldehyde and 100 ml of ethanol. Then, 1.14 g (30.1mmol) of sodium borohydride was added thereto with stirring underice-cooling and the mixture was stirred for 2 hours and then allowed tostand at room temperature overnight. After concentrating under reducedpressure, to the residue were added 100 ml of ethyl acetate and 100 mlof water, the mixture was shaken, and then the organic layer wasseparated. The aqueous layer was extracted once again with 100 ml ofethyl acetate, and the ethyl acetate layers were combined and thenwashed with 100 ml of water followed by 100 ml of saturated brine. Afterdrying over anhydrous magnesium sulfate, the mixture was concentratedunder reduced pressure to obtain 2.5 dimethoxybenzyl alcohol.

¹H-NMR (CDCl₃) δ: 3.77 (s, 3H), 3.82 (s, 3H), 4.65 (s, 2H), 6.79 (d, 1H,J=2.8 Hz), 6.80 (s, 1H), 6.89 (d, 1H, J=2.8 Hz).

(Step 2)

A 25 ml round-bottomed flask was charged with 1.0 g (2.96 mmol) of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 0.55 g (3.26mmol) of 2,5-dimethoxybenzyl alcohol, 2.18 g (16.87 mmol) ofdiisopropylethylamine, 10 ml of dichloromethane, and 889 mg (4.44 mmol)of EPPA and the mixture was stirred at room temperature for about 6days. To the reaction mixture was added 10 ml of water, the mixture wasshaken and the dichloromethane layer was separated. The aqueous layerwas extracted once again with 10 ml of dichloromethane, and the organiclayers were combined and washed with water (10 ml) followed by saturatedbrine (10 ml). After drying over anhydrous magnesium sulfate, themixture was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography (50 g, n-hexane-ethylacetate 3:1, V/V) to obtain 649 mg of the title compound (yield: 48%).

Elemental analysis: C₂₇H₂₇F₂NO₃

Calculated: C, 71.82; H, 6.03; N, 3.10.

Found: C, 71.61; H, 6.23; N, 2.93.

IR (KBr): 2952, 2834, 1716, 1603, 1507, 1466, 1347, 1274, 1224, 1178,1158, 1103, 1049, 1028, 825, 712, 579, 553 cm⁻¹.

Example 1613-Benzhydryl-1-(3,5-di-tert-butyl-2-methoxybenzyl)-4-piperidinone

A 25 ml round-bottomed flask was charged with 1.0 g (3.28 mmol) of3-benzhydryl-4-piperidinone hydrochloride, 0.91 g (3.61 mmol) of3,5-di-tert-butyl-2-methoxybenzyl alcohol, 2.42 g (18.7 mmol) ofdiisopropylethylamine, 10 ml of dichloromethane and 985 mg (4.92 mmol)of EPPA, and the mixture was stirred at room temperature for about 5days. To the reaction mixture was added with 10 ml of water, the mixturewas shaken and the dichloromethane layer was separated. The aqueouslayer was extracted once again with 10 ml of dichloromethane, and theorganic layers were combined and washed with water (10 ml) followed bysaturated brine (10 ml). After drying over anhydrous magnesium sulfate,the mixture was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography (50 g, n-hexane-ethylacetate 6:1, V/V) to obtain 512 mg of the title compound (yield: 32%).

mp 136-138° C.

Elemental analysis: C₃₄H₄₃NO₂

Calculated: C, 82.05; H, 8.71; N, 2.81.

Found: C, 81.97; H, 9.00; N, 2.59.

IR (KBr): 3431, 2960, 1719, 1477, 1361, 1231, 1011, 744, 703, 549 cm⁻¹.

¹H-NMR (CDCl₃) δ: 1.33 (s, 9H), 1.42 (s, 9H), 2.33-2.38 (m, 1H),2.46-2.59 (m, 2H), 2.64-2.73 (m, 2H), 2.79-2.84 (m, 1H), 3.36-3.41 (m,1H), 3.50 (d, 1H , J=13.2 Hz), 3.61 (d, 1H , J=13.2 Hz), 3.77 (s, 3H),4.62 (d, 1H , J=11.2 Hz), 7.08-7.16 (m, 6H), 7.21-7.30 (m, 4H),7.35-7.36 (m, 1H).

Example 162(+)-3-[Bis(4-fluorophenyl)methyl]-1-(5-bromo-2-methoxybenzyl)-4-piperidinone

The optically active title compound (412 mg) was obtained by subjecting1 g of3-[bis(4-fluorophenyl)methyl]-1-(5-bromo-2-methoxybenzyl)-4-piperidinoneobtained in Example 76 to HPLC (CHIRALPAK AD 50 mm ID×500 mm L,hexane/IPA).

Retention time: short

Optical purity: 99.6% ee.

mp 54-55° C.

[α]_(D)=+93.0° (c=1.049%, in CHCl₃).

Example 163(−)-3-[Bis(4-fluorophenyl)methyl]-1-(5-bromo-2-methoxybenzyl)-4-piperidinone

The optically active title compound (427 mg) was obtained by subjecting1 g of3-[bis(4-fluorophenyl)methyl]-1-(5-bromo-2-methoxybenzyl)-4-piperidinoneobtained in Example 76 to HPLC (CHIRALPAK AD 50 mm ID×500 mm L,hexane/IPA).

Retention time: long

Optical purity: 99.9% ee.

mp 52-53° C.

[α]_(D)=−94.3° (c=1.049%, in CHCl₃).

Example 1643-[Bis(4-fluorophenyl)methyl]-1-[2-(methylsulfanyl)benzyl]-4-piperidinone

(Step 1)

A 100 ml round-bottomed flask was charged with 2.12 g (39.2 mmol) ofsodium methylate, 50 ml of methanol, 5 g (35.7 mmol) of 2-mercaptobenzylalcohol and 5.57 g (39.2 mmol) of methyl iodide and the mixture wasallowed to stand at room temperature for about 3 days. Afterconcentrating under reduced pressure, 50 ml of ethyl acetate and 50 mlof water were added to the residue, the mixture was shaken, and then theethyl acetate layer was separated. The aqueous layer was extracted onceagain with 50 ml of ethyl acetate, and the organic layers were combined,washed with 50 ml of water followed by 50 ml of saturated brine. Afterdrying over anhydrous magnesium sulfate, the mixture was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography (200 g, n-hexane-ethyl acetate 4:1, V/V) to obtain 4.95 gof the title compound (yield: 90%).

(Step 2)

A 25 ml round-bottomed flask was charged with 1.0 g (2.96 mmol) of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 502 mg (3.26mmol) of 2-methylthiobenzyl alcohol, 2.18 g (16.87 mmol) ofdiisopropylethylamine, 10 ml of dichloromethane and 889 mg (4.44 mmol)of EPPA, the mixture was stirred at room temperature for about 5 days.To the reaction mixture was added 10 ml of water, the mixture was shakenand the dichloromethane layer was separated. The aqueous layer wasextracted once again with 10 ml of dichloromethane, and then the organiclayers were combined and washed with water (10 ml) followed by saturatedbrine (10 ml). The mixture was dried over an anhydrous magnesiumsulfate, concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (50 g, n-hexane-ethylacetate 4:1, V/V) to obtain 432 mg of the title compound (yield: 33%).

IR (KBr): 2923, 2803, 1715, 1603, 1508, 1469, 1440, 1347, 1224, 1189,1159, 1103, 1070, 1015, 830, 750, 578, 547 cm⁻¹.

¹H-NMR (CDCl₃)δ: 2.24-2.28 (m, 1H), 2.44-2.48 (m, 1H), 2.52-2.66 (m,2H), 2.54 (s, 3H), 3.05-3.15 (m, 2H), 3.40 (d, 1H, J=13.2 Hz), 3.68 (d,1H, J=12.4 Hz), 4.64 (d, 1H, J=11.2 Hz), 6.72-6.77 (m, 2H), 6.89-6.99(m, 4H), 7.03-7.13 (m, 2H), 7.24-7.26 (m, 2H), 7.30-7.35 (m, 2H).

Example 165 3-Benzhydryl-1-[2-(methylsulfanyl)benzyl]-4-piperidinone

According to the same treatment as that described with respect to3-[bis(4-fluorophenyl)methyl]-1-[2-(methylsulfanyl)benzyl]-4-piperidinone,a crude material was obtained by using 1.0 g (2.61 mmol) of3-benzhydryl-4-piperidinone hydrochloride, 442 mg (2.87 mmol) of2-methylthiobenzyl alcohol, 1.92 g (14.87 mmol) of diisopropylethylamineand 783 mg (3.91 mmol) of EPPA, and purified by silica gel columnchromatography (50 g, n-hexane-ethyl acetate 6:1, V/V) to obtain 812 mgof the title compound (yield: 77%).

IR (KBr): 3060, 3028, 2921, 2801, 1715, 1590, 1494, 1468, 1451, 1345,1323, 1240, 1190, 1135, 1089, 1068, 1034, 992, 911, 784, 747, 704, 549cm⁻¹.

Example 1663-[Bis(4-fluorophenyl)methyl]-1-(5-fluoro-2-methoxybenzyl)-4-piperidinone

(Step 1)

A 100 ml four-necked flask was charged with 5.0 g (32.4 mmol) of5-fluoro-2-methoxybenzaldehyde and 100 ml of ethanol, and 1.23 g (32.4mmol) of sodium borohydride was added thereto with stirring underice-cooling. Then, the mixture was stirred for 1 hour and allowed tostand at room temperature overnight. After concentrating under reducedpressure, 50 ml of ethyl acetate and 50 ml of water were added to theresidue, and the mixture was shaken and separated into layers. Theaqueous layer was extracted once again with 50 ml of ethyl acetate. Theethyl acetate layers were combined, and washed with 50 ml of waterfollowed by 50 ml of saturated brine. After drying over anhydrous sodiumsulfate, the mixture was concentrated under reduced pressure to obtain5-fluoro-2-methoxybenzyl alcohol.

¹H-NMR (CDCl₃) δ: 3.83 (s, 3H), 4.66 (d, 2H , J=6.4 Hz), 6.77-7.07 (m,3H).

(Step 2)

A 25 ml round-bottomed flask was charged with 1.0 g (2.96 mmol) of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 508 mg (3.26mmol) of 5-fluoro-2-methoxybenzyl alcohol, 2.18 g (16.87 mmol) ofdiisopropylethylamine, 10 ml of dichloromethane and 889 mg (4.44 mmol)of EPPA, and the mixture was stirred at room temperature for about 4days. To the reaction mixture was added 10 ml of water, and thedichloromethane layer was separated. The aqueous layer was extractedonce again with 10 ml of dichloromethane, and then the organic layerswere combined and washed with water (10 ml) followed by saturated brine(10 ml). The mixture was dried over an anhydrous magnesium sulfate andconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (50 g, n-hexane-ethyl acetate 4:1, V/V)to obtain 642 mg of the title compound (yield: 49.4%).

IR (KBr): 2484, 1729, 1604, 1508, 1224, 1159, 1028, 823, 720, 555 cm⁻¹.

¹H-NMR (CDCl₃) δ: 2.38-2.61 (m, 4H), 2.74-2.78 (m, 1H), 2.85-2.90 (m,1H), 3.26-3.31 (m, 1H), 3.52 (s, 2H), 3.74 (s, 3H), 4.58 (d, 1H, J=11.2Hz), 6.75 (m, 1H), 6.86-6.96 (m, 5H), 7.09-7.12 (m, 3H), 7.23-7.26 (m,2H).

Example 1673-[Bis(4-fluorophenyl)methyl]-1-[2-(methylsulfinyl)benzyl]-4-piperidinone

To a solution of 2 g (4.57 mmol) of3-[bis(4-fluorophenyl)methyl]-1-[2-(methylsulfanyl)benzyl]-4-piperidinonein 10 ml of NMP, was added 452 mg (0.91 mmol) of magnesiummonoperoxyphthalate (MMPP) in three portions at intervals of 20 minuteswith stirring under ice-cooling. The stirring was continued for 1 hourunder ice-cooling and then for 1 day at room temperature. After adding20 ml of ethyl acetate and 20 ml of water, the mixture was shaken, andthe organic layer was separated. The aqueous layer was extracted onceagain with 20 ml of ethyl acetate, and the ethyl acetate layers werecombined and washed twice with 10 ml of water and then twice with 20 mlof saturated brine. After drying over anhydrous magnesium sulfate, themixture was concentrated under reduced pressure, ethyl acetate was addedto the residue, and the precipitated crystals were collected byfiltration. The filtrate was dried under reduced pressure to obtain 239mg of the title compound (yield: 12%).

mp 187-189° C.

Elemental analysis: C₂₆H₂₅F₂N₂O₂S

Calculated: C, 68.85; H, 5.56; N, 3.09.

Found: C, 68.78; H, 5.66; N, 2.96.

IR(KBr) 3426, 2919, 2809, 2360, 1718, 1603, 1508, 1473, 1417, 1348,1224, 1159, 1121, 1065, 1028, 910, 830, 760, 732, 580, 560, 468 cm⁻¹.

Example 1683-Benzhydryl-1-[2-methoxy-5-(trifluoromethoxy)benzyl]-4-piperidinone

(Step 1)

To a solution of 660 mg (3 mmol) of2-methoxy-5-trifluoromethoxybenzaldehyde in 3 ml of THF and 3 ml ofmethanol was added 114 mg (3 mmol) of sodium borohydride with stirringunder ice-cooling, and the mixture was stirred for 0.5 hour. A saturatedaqueous ammonium chloride and ethyl acetate were added thereto and themixture was shaken. The ethyl acetate layer was washed with water, andthen with saturated brine. After drying over anhydrous magnesiumsulfate, the mixture was concentrated under reduced pressure to obtain2-methoxy-5-trifluoromethoxybenzyl alcohol as a colorless transparentoil.

¹H-NMR (CDCl₃) δ: 0.93 (t, 1H), 3.87 (s, 3H), 4.68 (d, 2H), 6.85 (d,2H), 7.11-7.14 (m, 1H), 7.21 (d, 1H).

(Step 2)

To a solution of 855 mg (2.84 mmol) of 3-benzhydryl-4-piperidinonehydrochloride, 960 mg (4.8 mmol) of EPPA, 630 mg (2.84 mmol) of2-methoxy-5-trifluoromethoxybenzyl alcohol in 7 ml of dichloromethanewas added 1.55 g (12 mmol) of diisopropylethylamine with stirring, andthe mixture was stirred at room temperature for 80 hours. To thereaction solution were added 50 ml of ethyl acetate, 30 ml of hexane and25 ml of water, the mixture was shaken, and the organic layer wasseparated and washed with an aqueous sodium bicarbonate followed bywater. After concentrating under reduced pressure, the residue waspurified by silica gel column chromatography (40 g, n-hexane-ethylacetate 4:1, V/V) to obtain 645.0 mg of the title compound as an oil(yield: 49%). This was dissolved in 5 ml of ethanol, 1.5 ml of 1N-HClwas added thereto, and the solvent was distilled off under reducedpressure. The residue was triturated with 2 ml of ethanol, and thecrystals were collected by filtration. After washing with small amountof ethanol, the filtrate was dried to obtain 666 mg of the hydrochlorideof the title compound as crystals (yield: 46%).

mp 174-175° C.

Elemental analysis: C₂₇H₂₆F₃NO₃.HCl (505.956)

Calculated: C, 64.09; H, 5.38; N, 2.77.

Found: C, 64.11; H, 5.53; N, 2.65.

¹H-NMR (CDCl₃) δ: 2.38-4.96 (m, 13H), 7.06-7.89 (m, 13H), 7.62,7.89(each s, total 1H).

Example 1693-[Bis(4-fluorophenyl)methyl]-1-[2-methoxy-5-(trifluoromethoxy)benzyl]-4-piperidinone

(Step 1)

A 25 ml round-bottomed flask was charged with 1.0 g (4.85 mmol) of2-hydroxy-5-(trifluoromethoxy)benzaldehyde, 8 ml of dimethylformamide(DMF) and 738 mg (5.34 mmol) of potassium carbonate, the mixture wasstirred for about 30 minutes, and then a solution of methyl iodide 758mg (5.34 mmol)/DMF 2 ml was added thereto under ice-cooling. The mixturewas stirred under ice-cooling for 1 hour and then at room temperaturefor 19 hours. To the reaction mixture was added 20 ml of ethyl acetateand 20 ml of water, the mixture was shaken and the organic layer wasseparated. The aqueous layer was extracted once again with 20 ml ofethyl acetate, and the organic layers were combined, and washed twicewith 20 ml of water and then twice with 20 ml of brine. The organiclayer was dried over MgSO₄ (anhydrous) and concentrated under reducedpressure to obtain 1.0 g of 2-methoxy-5-(trifluoromethoxy)benzaldehyde(yield: 93%).

¹H-NMR (CDCl₃) δ: 3.96 (s, 3H), 7.02 (d, 1H, J=8.8 Hz), 7.41 (d, 1H,J=9.2 Hz), 7.69(1H, s,), 10.44(1H, s).

(Step 2)

A 25 ml round-bottomed flask was charged with 996 mg (4.52 mmol) of2-methoxy-5-(trifluoromethoxy)benzaldehyde and 8 ml of tetrahydrofuran(THF), and a sodium borohydride 342 mg (9 mmol)/THF 2 ml was addedthereto with stirring under ice-cooling. The mixture was stirred underice-cooling for 1 hour and then at room temperature for 8 hours. Then, 2ml of methanol was added thereto under ice-cooling, and the mixture wasstirred at the same temperature for 30 minutes. To the reaction mixturewere added 20 ml of ethyl acetate and 20 ml of water, the mixture wasshaken and then the organic layer was separated. The aqueous layer wasextracted once again with 20 ml of ethyl acetate, and the organic layerswere combined, washed twice with 20 ml of water and then twice with 20ml of brine. The organic layer was dried over MgSO₄ (anhydrous) andconcentrated under reduced pressure to obtain 1.0 g of2-methoxy-5-trifluoromethoxybenzyl alcohol (yield: 85%).

¹H-NMR (CDCl₃) δ: 3.87 (s, 3H), 4.68 (s, 2H), 6.85 (d, 1H, J=9.2 Hz),7.13 (d, 1H, J=8.8 Hz), 7.21 (s, 1H).

(Step 3)

A 10 ml round-bottomed flask was charged with 608 mg (1.80 mmol) of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 400 mg (1.80mmol) of 2-methoxy-5-trifluoromethoxybenzyl alcohol, 1.33 g (10.3 mmol)of diisopropylethylamine, 4 ml of dichloromethane, and 540 mg (2.7 mmol)of EPPA, and the mixture was stirred at room temperature for 7 hours.Further, additional 180 mg (0.9 mmol) of EPPA was added, and the mixturewas allowed to stand for 2 days. To the reaction mixture was added 20 mlof water, the mixture was shaken, and the dichloromethane layer wasseparated. The aqueous layer was extracted once again with 20 ml ofdichloromethane. The organic layers were combined and washed with water(20 ml) followed by saturated brine (20 ml). After drying over anhydrousmagnesium sulfate, the mixture was concentrated under reduced pressure,the residue was subjected to silica gel column chromatography (50 g,n-hexane-ethyl acetate 5:1, V/V) to obtain the title compound.

¹H-NMR (CDCl₃) δ: 2.40-2.45 (m, 2H), 2.49-2.61 (m, 2H), 3.30 (m, 1H),3.53 (s, 2H), 3.77 (s, 3H), 4.56 (d, 1H, J=11.2 Hz), 6.81 (d, 1H, J=9.2Hz), 6.87(dd, 2H, J=8.6 Hz, J=8.8 Hz), 6.94(dd, 2H, J=8.6 Hz, J=8.8 Hz),7.07-7.12 (m, 3H), 7.22-7.25 (m, 3H).

The title compound was converted into the hydrochloride by aconventional method to obtain 210 mg of the hydrochloride of the titlecompound.

Elemental analysis: C₂₇H₂₅F₅NO₃.HCl.0.5H₂O

Calculated: C, 58.86; H, 4.76; N, 2.54.

Found: C, 58.76; H, 4.70; N, 2.42.

Example 170 3-Benzhydryl-1-(2-ethoxy-6-methoxybenzyl)-4-piperidinone

(Step 1)

To a mixture of 3.04 g (20 mmol) of 2-hydroxy-6-methoxybenzaldehyde, 25ml of dimethylformamide (DMF) and 5 ml of ethyl iodide was added 840 mg(21 mmol, washed with hexane) of 60% sodium hydride in oil with stirringat room temperature. The mixture was stirred at room temperature forabout 13 hours. To the reaction mixture were added 100 ml of isopropylether, 100 ml of ether and 200 ml of water, the mixture was shaken andthe organic layer was separated and washed with 20 ml of 0.1N—NaOH. Theorganic layer was dried over MgSO₄ (anhydrous), and then concentratedunder reduced pressure to obtain 2.57 g of2-ethoxy-6-methoxybenzaldehyde (yield: 72%) as a pale yellow oil.

¹H-NMR (CDCl₃) δ: 1.46(t, 3H), 3.90 (s, 3H), 4.12(q, 2H), 6.56 (d, 2H),7.42(t, 1H, ), 10.53 (s, 1H).

(Step 2)

To a mixture of 2.56 g (14.2 mmol) of 2-ethoxy-6-methoxybenzaldehyde, 20ml of tetrahydrofuran (THF) and 30 ml of methanol was added 380 mg (10mmol) of sodium borohydride with stirring under ice-cooling. The mixturewas stirred under ice-cooling for 4 hours and then at room temperaturefor 20 hours. The reaction mixture was concentrated under reducedpressure, and 50 ml of ethyl acetate and 20 ml of water were added tothe residue. The mixture was shaken and the organic layer was separated,and washed with water. The organic layer was dried over MgSO₄(anhydrous), and then concentrated under reduced pressure to obtain 2.47g of 2-ethoxy-6-methoxybenzyl alcohol (yield: 96%).

¹H-NMR (CDCl₃) δ: 1.42(t, 3H), 2.56(t, 1H), 3.84 (s, 3H), 4.06(q, 2H),4.80 (d, 2H), 6.54 (d, 2H), 7.19(t, 1H).

(Step 3)

To 906 mg (3.0 mmol) of 3-benzhydryl-4-piperidinone hydrochloride wasadded 6 ml of dichloromethane, and then 1.0 g (7.8 mmol) ofdiisopropylethylamine was added to the mixture with stirring at roomtemperature. After dissolution, 728 mg (4.0 mmol) of2-ethoxy-6-methoxybenzyl alcohol and 1 g (5 mmol) of EPPA were added andthe mixture was stirred for 120 hours. To the reaction mixture wereadded 40 ml of isopropyl ether, 40 ml of ethyl acetate and 15 ml ofwater, the mixture was shaken, and the organic layer was separated, andwashed with sodium bicarbonate. After drying over anhydrous magnesiumsulfate, the mixture was concentrated under reduced pressure, theresidue was washed twice with 20 ml of hexane. After addition of 10 mlof ethanol, the precipitated crystals were collected by filtration,washed with ethanol and then dried to obtain 0.55 g of the titlecompound as colorless crystals (yield: 43%).

mp 137-138° C.

¹H-NMR (CDCl₃) δ: 1.28 (s, 3H), 2.40-4.58 (s, 3H), 2.70-2.74 (m, 1H),2.85-2.88 (m, 2H), 3.36-3.41 (m, 1H), 3.71 (s, 3H), 3.72 (s, 2H),3.93(q, 2H), 4.53 (d, 1H), 6.50(t, 2H), 7.09-7.30 (m, 11H).

Elemental analysis: C₂₈H₃₁NO₃.0.1H₂O

Calculated: C, 77.96; H, 7.29; N, 3.25.

Found: C, 77.77; H, 7.24; N, 3.11.

Example 1713-[Bis(4-fluorophenyl)methyl]-1-(3,5-dibromo-2-methoxybenzyl)-4-piperidinone

(Step 1)

A 35 ml round-bottomed flask was charged with 2.0 g (7.12 mmol) of3,5-dibromosalicylaldehyde, 15 ml of dimethylformamide (DMF) and 1.1 g(7.86 mmol) of potassium carbonate, the mixture was stirred for about 30minutes, and then a methyl iodide 1.1 g (7.86 mmol)/DMF 2 ml solutionwas added thereto under ice-cooling. The mixture was stirred underice-cooling for about 1 hour and then at room temperature for 14 hours.To the reaction mixture were added 20 ml of ethyl acetate and 20 ml ofwater, the mixture was shaken and the organic layer was separated. Theaqueous layer was extracted once again with 20 ml of ethyl acetate, andthe organic layers were combined, and washed twice with 20 ml of waterand twice with 20 ml of brine. The organic layer was dried over MgSO₄(anhydrous) and then concentrated under reduced pressure to obtain 1.4 gof 3,5-dibromo-2-methoxybenzaldehyde (yield: 65%).

¹H-NMR (CDCl₃) δ: 3.99 (s, 3H), 7.91 (d, 1H, J=2.4 Hz), 7.94 (d, 1H,J=2.4 Hz), 10.28(1H, s).

(Step 2)

A 25 ml round-bottomed flask was charged with 1.2 g (4.08 mmol) of3,5-dibromo-2-methoxybenzaldehyde and 6 ml of tetrahydrofuran (THF), anda sodium borohydride 309 mg (8.16 mmol)/EtOH 6 ml was added thereto withstirring under ice-cooling. The mixture was stirred under ice-coolingfor about 1 hour and then at room temperature for 3 hours. To thereaction solution were added 20 ml of ethyl acetate and 20 ml of water,the mixture was shaken and the organic layer was separated. The aqueouslayer was extracted once again with 20 ml of ethyl acetate, and theorganic layers were combined, and washed twice with 20 ml of water andtwice with 20 ml of brine. The organic layer was dried over MgSO₄(anhydrous) and concentrated under reduced pressure. Diisopropyl etherwas added to the residue and the precipitated crystals were collected byfiltration and dried under reduced pressure to obtain 0.7 g of3,5-dibromo-2-methoxybenzyl alcohol (yield: 58%).

¹H-NMR (CDCl₃) δ: 3.85 (s, 3H), 4.72 (s, 2H), 7.51 (d, 1H, J=2.4 Hz),7.64 (d, 1H, J=2.4 Hz).

(Step 3) A 10 ml round-bottomed flask was charged with 200 mg (0.68mmol) of 3,5-dibromo-2-methoxybenzyl alcohol, 228 mg (0.68 mmol) of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 498 mg (3.85mmol) of diisopropylethylamine and 2 ml of dichloromethane, 203 mg (1.01mmol) of EPPA was added thereto with stirring and the mixture wasstirred at room temperature for 3 days. To the reaction mixture wereadded 20 ml of dichloromethane and 20 ml of water, the mixture wasshaken and the dichloromethane layer was separated. The aqueous layerwas extracted once again with 20 ml of dichloromethane and the organiclayers were combined and washed with water (20 ml) followed by saturatedbrine (20 ml). After drying over anhydrous magnesium sulfate, themixture was concentrated under reduced pressure, the residue wassubjected to silica gel column chromatography (50 g, n-hexane-ethylacetate 4:1, V/V) to obtain 0.21 g of the title compound (yield: 54%).

Elemental analysis: C₂₆H₂₃Br₂F₂NO₂.0.3H₂O

Calculated: C, 53.41; H, 407; N, 2.40.

Found: C, 53.44; H, 401; N, 2.36.

IR (KBr): 2934, 1718, 1604, 1508, 1464, 1419, 1346, 1225, 1158, 999,826, 552 cm⁻¹.

Example 172 1,3-Bis[bis(4-fluorophenyl)methyl]-4-piperidinone

A 10 ml round-bottomed flask was charged with 652 mg (2.96 mmol) of4,4′-difluorobenzhydrol, 1.0 g (2.96 mmol) of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 2.18 g (16.9mmol) of diisopropylethylamine and 3 ml of dichloromethane, and EPPA 889mg (4.44 mmol)/dichloromethane 4 ml was added thereto with stirring andthe mixture was stirred for 3 days at room temperature. To the reactionmixture were added 20 ml of dichloromethane and 20 ml of water, themixture was shaken, and the dichloromethane layer was separated. Theaqueous layer was extracted once again with 20 ml of dichloromethane,and the organic layers were combined and washed with water (20 ml)followed by saturated brine (20 ml). After drying over anhydrousmagnesium sulfate, the mixture was concentrated under reduced pressure,the residue was subjected to silica gel column chromatography (50 g,n-hexane-ethyl acetate, 6:1, V/V) to obtain 0.24 g of the title compound(yield: 16%).

¹H-NMR (CDCl₃) δ: 2.26-2.30 (m, 1H), 2.44-2.74 (m, 5H), 3.33-3.38 (m,1H), 4.33 (s, 1H), 4.54 (d, 1H, J=10.8 Hz), 6.82-6.97 (m, 8H), 7.00-7.05(m, 2H), 7.17-7.20 (m, 2H), 7.23-7.34 (m, 4H), 7.63 (d, 1H, J=2.8 Hz).

Elemental analysis: C₃₁H₂₅F₄NO.0.2H₂O

Calculated: C, 73.42; H, 5.05; N, 2.76.

Found: C, 73.55; H, 5.16; N, 2.57.

IR (KBr): 1717, 1604, 1508, 1226, 1158, 827, 734, 553 cm⁻¹.

Example 173 3-Benzhydryl-1-(3,5-dichloro-2-methoxybenzyl)-4-piperidinone

(Step 1)

A 35 ml round-bottomed flask was charged with 2.0 g (10.5 mmol) of3,5-dichloro-2-hydroxybenzaldehyde, 15 ml of dimethylformamide (DMF) and1.6 g (11.5 mmol) of potassium carbonate, the mixture was stirred for 30minutes, and a solution of methyl iodide 1.63 g (11.5 mmol)/DMF 5 ml wasadded thereto under ice-cooling. The mixture was stirred under withcooling in ice for about 1 hour and then at room temperature for 19hours. To the reaction mixture were added 20 ml of ethyl acetate and 20ml of water, the mixture was shaken and the organic layer was separated.The aqueous layer was extracted once again with 20 ml of ethyl acetate,and the organic layers were combined, and washed twice with 20 ml ofwater and twice with 20 ml of brine. The organic layer was dried overMgSO₄ (anhydrous) and concentrated under reduced pressure, and ethylacetate was added to the residue. The precipitated crystals werecollected by filtration and dried to obtain 0.89 g of3,5-dichloro-2-methoxybenzaldehyde (yield: 42%).

¹H-NMR (CDCl₃) δ: 4.00 (s, 3H), 7.63 (d, 1H, J=2.4 Hz), 7.72 (d, 1H,J=2.8 Hz), 10.31(1H, s).

(Step 2)

A 25 ml round-bottomed flask was charged with 1.0 g (4.88 mmol) of3,5-dichloro-2-methoxybenzaldehyde, 5 ml of tetrahydrofuran (THF) and 5ml of ethanol, and 369 mg (9.75 mmol) of sodium borohydride was addedthereto with stirring under ice-cooling in ice. The mixture was stirredunder ice-cooling for about 1 hour and then at room temperature for 3hours. To the reaction mixture were added 20 ml of ethyl acetate and 20ml of water, the mixture was shaken and the organic layer was separated.The aqueous layer was extracted once again with 20 ml of ethyl acetate,the organic layers were combined, and washed twice with 20 ml of waterand twice with 20 ml of brine. The organic layer was dried over MgSO₄(anhydrous) and concentrated under reduced pressure, and diisopropylether was added to the residue. The precipitated crystals were collectedby filtration and dried under reduced pressure to obtain 580 mg of3,5-dichloro-2-methoxybenzyl alcohol (yield: 58%).

¹H-NMR (CDCl₃) δ: 3.87 (s, 3H), 4.70 (d, 2H, J=6.0 Hz), 7.30-7.32 (m,2H).

(Step 3)

A 5 ml round-bottomed flask was charged with 200 mg (0.97 mmol) of3,5-dichloro-2-methoxybenzyl alcohol, 292 mg (0.97 mmol) of3-benzhydryl-4-piperidinone hydrochloride, 712 mg (5.51 mmol) ofdiisopropylethylamine and 1 ml of dichloromethane, and a solution ofEPPA 203 mg (1.01 mmol)/dichloromethane 1 ml was added thereto withstirring and the mixture was stirred at room temperature for 2 days. Tothe reaction solution were added 20 ml of dichloromethane and 20 ml of asaturated aqueous sodium bicarbonate, the mixture was shaken, and thedichloromethane layer was separated. The aqueous layer was extractedonce again with 20 ml of dichloromethane, and the organic layers werecombined, and washed with 20 ml of a saturated aqueous sodiumbicarbonate, 20 ml of water and then 20 ml of saturated brine. Afterdrying over anhydrous magnesium sulfate, the mixture was concentratedunder reduced pressure, the residue was subjected to silica gel columnchromatography (50 g, n-hexane-ethyl acetate 4:1, V/V) to obtain 0.16 gof the title compound (yield: 35%).

¹H-NMR (CDCl₃) δ: 2.42-2.57 (m, 4H), 2.77-2.87 (m, 2H), 3.41-3.56 (m,3H), 3.80 (s, 3H), 4.55 (d, 1H, J=10.8 Hz), 7.12-7.31 (m, 12H).

Elemental analysis: C₂₆H₂₅Cl₂NO₂

Calculated: C, 68.72; H, 5.55; N, 3.08.

Found: C, 68.40; H, 5.53; N, 3.01.

IR (KBr): 1720, 1494, 1468, 1422, 999, 840, 747, 704, 547 cm⁻¹.

Example 174 3-Benzhydryl-1-(3,5-dibromo-2-methoxybenzyl)-4-piperidinone

A 5 ml round-bottomed flask was charged with 200 mg (0.68 mmol) of3,5-dibromo-2-methoxybenzyl alcohol, 204 mg (0.68 mmol) of3-benzhydryl-4-piperidinone hydrochloride, 498 mg (3.85 mmol) ofdiisopropylethylamine and 2 ml of dichloromethane, and 203 mg (1.01mmol) of EPPA was added thereto with stirring and the mixture wasstirred at room temperature for 2 days. To the reaction mixture wereadded 20 ml of dichloromethane and 20 ml of saturated aqueous sodiumbicarbonate, the mixture was shaken, and the dichloromethane layer wasseparated. The aqueous layer was extracted once again with 20 ml ofdichloromethane, and then the organic layers were combined and washedsuccessively with 20 ml of saturated aqueous sodium bicarbonate, 20 mlof water and then 20 ml of saturated brine. After drying over anhydrousmagnesium sulfate, the mixture was concentrated under reduced pressure,the residue was subjected to silica gel column chromatography (50 g,n-hexane-ethyl acetate 4:1, V/V) to obtain 0.18 g of the title compound(yield: 37%).

Elemental analysis: C₂₆H₂₅Br₂NO₂.0.2H₂O

Calculated: C, 57.10; H, 4.68; N, 2.56.

Found: C, 56.98; H, 4.58; N, 2.64.

IR (KBr): 2937, 1720, 1599, 1494, 1463, 1418, 1345, 1154, 998, 746, 704,546 cm⁻¹.

Example 175 3-Benzhydryl-1-(5-isopropyl-2-methoxybenzyl)-4-piperidinone

(Step 1)

A 35 ml round-bottomed flask was charged with 2.0 g (11.2 mmol) of2-methoxy-5-isopropylbenzaldehyde and 15 ml of ethanol, and 849 mg (22.4mmol) of sodium borohydride was added thereto with stirring underice-cooling. The mixture was stirred under ice-cooling for about 1 hourand then at room temperature for 3 hours. To the reaction mixture wereadded 20 ml of ethyl acetate and 20 ml of water, the mixture was shakenand the organic layer was separated. The aqueous layer was extractedonce again with 20 ml of ethyl acetate, and the organic layers werecombined and washed twice with 20 ml of water and twice with 20 ml ofbrine. The organic layer was dried over MgSO₄ (anhydrous) andconcentrated under reduced pressure to obtain 1.70 g of2-methoxy-5-isopropylbenzyl alcohol (yield: 84%).

¹H-NMR (CDCl₃) δ: 1.22 (s, 3H), 1.23 (s, 3H), 2.83-2.90 (m, 1H), 3.84(s, 3H), 4.68 (s, 2H), 6.82 (d, 1H, J=8.0 Hz), 7.11-7.14 (m, 2H).

(Step 2)

A 25 ml round-bottomed flask was charged 800 mg (4.44 mmol) of2-methoxy-5-isopropylbenzyl alcohol, 1.34 g (4.44 mmol) of3-benzhydryl-4-piperidinone hydrochloride, 3.27 g (25.3 mmol) ofdiisopropylethylamine and 4 ml of dichloromethane, 1.33 g (6.66 mmol) ofEPPA was added thereto with stirring and the mixture was stirred at roomtemperature for 2 days. To the reaction mixture were added 20 ml ofdichloromethane and 20 ml of a saturated aqueous sodium bicarbonate, themixture was shaken, and the dichloromethane layer was separated. Theaqueous layer was extracted once again with 20 ml of dichloromethane,and the organic layers were combined and washed successively with 20 mlof a saturated aqueous sodium bicarbonate, 20 ml of water and 20 ml ofsaturated brine. After drying over anhydrous magnesium sulfate, themixture was concentrated under reduced pressure, the residue wassubjected to silica gel column chromatography (50 g, n-hexane-ethylacetate 5:1, V/V) to obtain 0.36 g of the title compound (yield: 19%).

¹H-NMR (CDCl₃) δ: 1.23-1.25 (m, 6H), 2.41-2.52 (m, 3H), 2.64-2.68 (m,1H), 2.77-2.90 (m, 3H), 3.41-3.42 (m, 1H), 3.56 (s, 2H), 3.74 (s, 3H),4.59 (d, 1H, J=10.8 Hz), 6.79 (d, 1H, J=8.0 Hz), 7.09-7.31 (m, 12H).

Elemental analysis: C₂₉H₃₃NO₂

Calculated: C, 81.46; H, 7.78; N, 3.28.

Found: C, 81.43; H, 7.80; N, 3.22.

IR (KBr): 3061, 3028, 3002, 2959, 2928, 2869, 2835, 2799, 1717, 1599,1503, 1452, 1424, 1383, 1363, 1344, 1289, 1252, 1183, 1130, 1089, 1068,1033, 996, 867, 814, 782, 746, 704, 548 cm⁻¹.

Example 176 3-Benzhydryl-1-(2-methoxy-5-nitrobenzyl)-4-piperidinone

A mixture of 9.1 g (30 mmol) of 3-benzhydryl-4-piperidinonehydrochloride, 7.38 g (30.0 mmol) of 2-methoxy-5-nitrobenzyl bromide and5 g (60 mmol) of sodium hydrogen carbonate in 40 ml of dimethylformamide(DMF) was stirred for 30 hours at room temperature. To the reactionmixture were added 250 ml of ethyl acetate, 400 ml of water and 50 ml ofhexane, the mixture was shaken, and the organic layer was separated, andwashed with water. The organic layer was dried over MgSO₄ (anhydrous)and concentrated under reduced pressure. Ethanol was added to theresidue and the precipitated crystals were collected by filtration anddried to obtain 12.0 g of the title compound as crystals (yield: 93%).

mp 119-120° C.

¹H-NMR (CDCl₃) δ: 2.42-4.50 (m, 2H), 2.54-2.67 (m, 2H), 2.78-2.82 (m,2H), 3.44-3.50 (m, 1H), 3.56 (s, 2H), 3.87 (s, 3H), 4.56 (d, 1H, J=11.2Hz), 6.87 (d, 1H, J=8.8 Hz), 7.05-7.32 (m, 10H), 8.16(dd, 1H, J=3.2 Hz,J=2.8 Hz), 8.33 (d, 1H)

Elemental analysis: C₂₆H₂₆N₂O₄

Calculated: C, 72.54; H, 6.09; N, 6.51.

Found: C, 72.37; H, 5.92; N, 6.41.

Example 177 1-(5-Amino-2-methoxybenzyl)-3-benzhydryl-4-piperidinone

To a solution of 1.83 g (4.26 mmol) of3-benzhydryl-1-(2-methoxy-5-nitrobenzyl)-4-piperidinone in 10 ml of THF,was added a suspension of 5% Pd—C 520 mg (dried material)/methanol 15ml. The mixture was stirred under atmospheric pressure in a hydrogenstream. After the catalyst was filtered off, 0.71 ml of conc.hydrochloric acid, 40 ml of toluene and 50 ml of ethanol were added andthe mixture was concentrated under reduced pressure. To the residue wasadded 50 ml of an ethanol/ethyl acetate (1/4) solvent mixture, and thecrystals were collected by filtration, washed with the same solvent anddried to obtain 1.76 g of the hydrochloride of the title compound ascolorless crystals (yield: 88%).

mp 198-200° C.

¹H-NMR (CDCl₃) δ: 2.40-4.60 (m, 13H), 7.06-7.56 (m, 13H), 10.30(br, 2H).

Elemental analysis: C₂₆H₂₈N₂O₄.2HCl.0.5H₂O

Calculated: C, 64.73; H, 6.48; N, 5.81.

Found: C, 65.01; H, 6.54; N, 5.64.

Example 178N-[3-[(3-Benzhydryl-4-oxo-1-piperidinyl)methyl]-4-methoxyphenyl]-N-(methylsulfonyl)methanesulfonamide

In 5 ml of dichloromethane, 284 mg (0.6 mmol) of1-(5-amino-2-methoxybenzyl)-3-benzhydryl-4-piperidinone.2HCl salt wasstirred with ice-cooling, and 404 mg (4 mmol) of triethylamine was addedthereto. After dissolution, 276 mg (2.4 mmol) of methanesulfonylchloride was added and the mixture was stirred for 2 hours. To thereaction mixture were added 40 ml of isopropyl ether, 40 ml of ethylacetate and 30 ml of water, the mixture was shaken, and the organiclayer was separated, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure, and then the residue was subjectedto silica gel column chromatography (40 g, n-hexane-ethyl acetate2:1-1:1, V/V) to obtain 220 mg of the title compound as colorlesscrystals (yield: 66%).

mp 132-135° C.

¹H-NMR (CDCl₃) δ: 2.38-2.53 (m, 3H), 2.71-2.78 (m, 3H), 3.40-3.48 (m,7H), 2.56 (s, 2H), 3.79 (s, 3H), 4.58 (d, 1H), 6.89 (d, 1H), 7.13-7.31(m, 11H), 7.39 (d, 1H).

Elemental analysis: C₂₈H₃₂N₂O₆S₂

Calculated: C, 60.41; H, 5.79; N, 5.03.

Found: C, 60.13; H, 5.67; N, 4.97.

Example 179N-[3-[(3-Benzhydryl-4-oxo-1-piperidinyl)methyl]-4-methoxyphenyl]acetamide

In 2 ml of dimethylformamide, 437 mg (1.0 mmol) of1-(5-amino-2-methoxybenzyl)-3-benzhydryl-4-piperidinone.2HCl salt wasstirred, and 0.5 ml of pyridine and 0.3 ml of acetic anhydride wereadded thereto at room temperature. After stirring for 0.5 hours, to thereaction mixture were added 60 ml of ethyl acetate and 30 ml of water,the mixture was shaken, and the organic layer was separated. The organiclayer was washed with an aqueous sodium bicarbonate, dried overanhydrous magnesium sulfate and then concentrated under reducedpressure. The residue was washed with isopropyl ether and dried toobtain 280 mg of the title compound as a pale yellow solid (yield: 63%).

¹H-NMR (CDCl₃) δ: 2.19 (s, 3H), 2.37-2.43 (m, 1H), 2.49-2.55 (m, 2H),2.62-2.66 (m, 1H), 2.72-2.78 (m, 1H), 2.82-2.88 (m, 1H), 3.38-3.43 (m,1H), 3.74 (s, 3H), 4.62 (d, 1H), 6.79 (d, 1H), 7.10(br, 1H), 7.11-7.42(m, 12H).

Example 1803-Benzhydryl-1-[5-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methoxybenzyl]-4-piperidinone

A mixture of 310 mg (0.66 mmol) of1-(5-amino-2-methoxybenzyl)-3-benzhydryl-4-piperidinone.2HCl salt, 103mg (0.90 mmol) of acetonylacetone, 107 mg (0.90 mmol) of sodium acetateand 3 ml of acetic acid was stirred at room temperature for 1 hour. Thereaction mixture was poured into an excessive amount of an aqueoussodium hydrogen carbonate and the mixture was extracted with ethylacetate. After drying over anhydrous magnesium sulfate, the mixture wasconcentrated under reduced pressure, and the residue was subjected tosilica gel column chromatography (25 g, n-hexane-ethyl acetate 2:1, V/V)to obtain 197 mg of the title compound as a colorless solid (yield:63%).

¹H-NMR (CDCl₃) δ: 2.01 (s, 3H), 2.37-2.43 (m, 1H), 2.46-2.55 (m, 2H),2.63-2.68 (m, 1H), 2.70-2.77 (m, 1H), 2.81-2.85 (m, 1H), 3.39-3.44 (m,1H), 3.60 (s, 2H), 3.83 (s, 3H), 4.58 (d, 1H), 5.90 (s, 2H), 6.91 (d,1H), 7.07-7.30 (m, 12H).

Elemental analysis: C₃₂H₃₄N₂O₂.0.1H₂O

Calculated: C, 80.00; H, 7.18; N, 5.83.

Found: C, 79.76; H, 7.33; N, 5.58.

Example 1813-[Bis(4-fluorophenyl)methyl]-1-(5-isopropyl-2-methoxybenzyl)-4-piperidinone

A 25 ml round-bottomed flask was charged with 1.5 g (4.44 mmol) of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 0.80 g (4.44mmol) of 5-isopropyl-2-methoxybenzyl alcohol, 3.27 g (25.3 mmol) ofdiisopropylethylamine, 6 ml of dichloromethane and 1.33 g (6.66 mmol) ofEPPA, the mixture was stirred at room temperature for about 2 days. Tothe reaction mixture were added 20 ml of dichloromethane and 20 ml ofsaturated brine, the mixture was shaken and the dichloromethane layerwas separated. The aqueous layer was extracted once again with 20 ml ofdichloromethane, and the organic layers were combined and washed with 20ml of a saturated aqueous sodium hydrogen carbonate, 20 ml of water and20 ml of saturated brine. After drying over anhydrous magnesium sulfate,the mixture was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography (50 g, n-hexane-ethylacetate 6:1, V/V). The resultant compound was treated with hydrochloricacid to obtain 1.24 g of the hydrochloride of the title compound (yield:56%).

IR (KBr): 2962, 2369, 1730, 1604, 1509, 1462, 1260, 1224, 1159, 1027,823, 579, 554 cm⁻¹.

Example 1823-[Bis(4-fluorophenyl)methyl]-1-(5-bromo-2-ethoxybenzyl)-4-piperidinone

(Step 1)

A 100 ml round-bottomed flask was charged with 5.0 g (21.8 mmol) of5-bromo-2-ethoxybenzaldehyde, 25 ml of ethanol and 25 ml of THF, and 825mg (21.8 mmol) of sodium borohydride was added thereto with stirringunder ice-cooling. The mixture was stirred under ice-cooling for about 1hour and then at room temperature for 3 hours. The reaction solution wasconcentrated under reduced pressure, and to the residue were added 25 mlof ethyl acetate and 25 ml of water, the mixture was shaken, and thenthe organic layer was separated. The aqueous layer was extracted onceagain with 25 ml of ethyl acetate, and then the organic layers werecombined, and then washed with 25 ml of water and 25 ml of saturatedbrine. The organic layer was dried over MgSO₄ (anhydrous) andconcentrated under reduced pressure to obtain 2.3 g of5-bromo-2-ethoxybenzyl alcohol (yield: 46%).

¹H-NMR (CDCl₃) δ: 1.43(t, J=6.8 Hz, 3H), 1.23 (s, 3H), 4.06(q, 2H), 4.65(d, J=6.8 Hz, 2H), 6.73 (d, J=8.8 Hz, H), 7.34(dd, J=2.4 Hz, J=8.8 Hz),7.41 (d, J=2.8 Hz, 1H).

(Step 2)

A 25 ml round-bottomed flask was charged with 1.0 g (2.96 mmol) of5-bromo-2-ethoxybenzyl alcohol, 752.6 mg (3.26 mmol) of3-[bis(4-fluorophenyl)methyl]-4-piperidinone hydrochloride, 2.18 g (16.9mmol) of diisopropylethylamine and 6 ml of dichloromethane, and 889 mg(4.44 mmol) of EPPA dissolved in 4 ml of dichloromethane was added withstirring, and the mixture was stirred at room temperature for 6 days. Tothe reaction mixture were added 20 ml of dichloromethane and 20 ml of asaturated aqueous sodium bicarbonate, the mixture was shaken, and thedichloromethane layer was separated. The aqueous layer was extractedonce again with 20 ml of dichloromethane, and then the organic layerswere combined and washed successively with 20 ml of a saturated aqueoussodium bicarbonate, 20 ml of water and 20 ml of saturated brine. Afterdrying over anhydrous magnesium sulfate, the mixture was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (50 g, n-hexane-ethyl acetate 4:1, V/V) to obtainthe title compound.

¹H-NMR (CDCl₃) δ: 1.19-1.35 (m, 3H), 2.40-2.44 (m, 2H), 2.50-2.58 (m,2H), 2.80-2.88 (m, 2H), 3.30 (m, 1H), 3.45-3.52 (m, 3H), 3.90-3.96(q,J=6.8 Hz, 2H), 4.55 (d, 1H, J=11.2 Hz), 6.68 (d, 1H, J=8.8 Hz),6.87-6.96 (m, 4H), 7.06-7.10 (m, 2H), 7.23-7.26 (m, 2H), 7.32(dd, 1H,J=2.4 Hz, J=8.8 Hz), 7.48 (d, 1H, J=2.4 Hz).

After treatment with hydrochloric acid, 0.37 g of the hydrochloride ofthe title compound was obtained (yield: 23%).

Elemental analysis: C₂₇H₂₆ Br F₂NO₂.HCl

Calculated: C, 58.87; H, 4.94; N, 2.54.

Found: C, 58.73; H, 5.01; N, 2.45.

IR (KBr): 2981, 2444, 2389, 1733, 1605, 1508, 1474, 1454, 1418, 1398,1341, 1315, 1280, 1262, 1226, 1189, 1161, 1140, 1088, 1044, 1015, 990,966, 862, 826, 812, 782, 734, 644, 580, 559, 539, 507, 480 cm⁻¹.

Example 183N-[3-[(3-Benzhydryl-4-oxo-1-piperidinyl)methyl]-4-methoxyphenyl]methanesulfonamide

In 5 ml of pyridine, 473 mg (1.0 mmol) of1-(5-amino-2-methoxybenzyl)-3-benzhydryl-4-piperidinone.2HCl salt wasstirred at room temperature, 150 mg (1.3 mmol) of methanesulfonylchloride was added thereto and the mixture was stirred for 1 hour. Tothe reaction mixture was added 0.2 ml of water, the mixture wasconcentrated under reduced pressure, and 40 ml of ethyl acetate and 30ml of an aqueous sodium hydrogen carbonate were added to the residue.The mixture was shaken, the organic layer was separated, dried overanhydrous magnesium sulfate and concentrated under reduced pressure, andthe residue was subjected to silica gel column chromatography (25 g,n-hexane-ethyl acetate 1:1, V/V) to obtain 408 mg of the title compoundas a colorless solid (yield: 85%).

mp 132-135° C.

¹H-NMR (CDCl₃) δ: 2.36-2.43 (m, 3H), 2.54-2.63 (m, 3H), 2.71-2.77 (m,1H), 2.85-2.91 (m, 1H), 2.94 (s, 3H), 3.39-3.44 (m, 1H), 3.51 (d, 1H),3.57 (d, 1H), 3.77 (s, 3H), 4.64 (d, 1H), 6.20(br, 1H), 6.81 (d, 1H),7.11-7.31 (m, 12H).

Elemental analysis: C₂₇H₃₀N₂O₄S.0.2H₂O

Calculated: C, 67.25; H, 6.35; N, 5.81.

Found: C, 67.20; H, 6.26; N, 5.53.

Example 184 3-Benzhydryl-1-(2-hydroxy-5-nitrobenzyl)-4-piperidinone

In 15 ml of dimethylformamide (DMF), 3.02 g (10 mmol) of3-benzhydryl-4-piperidinone hydrochloride, 1.88 g (10 mmol) of2-hydroxy-5-nitrobenzyl bromide and 3.36 g (40 mmol) of sodium hydrogencarbonate were stirred at room temperature for 15 hours. To the reactionmixture were added 150 ml of ethyl acetate and 150 ml of water, themixture was shaken and the organic layer was separated, and washed withwater. The organic layer was dried over MgSO₄ (anhydrous) andconcentrated under reduced pressure, and 10 ml of ethanol was added tothe residue. The precipitated crystals were collected by filtration anddried to obtain 2.95 g of the title compound as crystals (yield: 71%).

mp 177-178° C.

¹H-NMR (CDCl₃) δ: 2.49-4.65 (m, 3H), 2.80-2.84 (m, 1H), 2.91(br, 2H),3.51-3.56 (m, 1H), 3.78 (s, 2H), 4.41 (d, 1H), 6.95 (d, 1H), 7.11-7.31(m, 10H), 7.88 (d, 1H), 8.12(dd, 1H).

Elemental analysis: C₂₅H₂₄N₂O₄

Calculated: C, 72.10; H, 5.81; N, 6.73.

Found: C, 72.03; H, 5.75; N, 6.46.

Example 185 3-Benzhydryl-1-(2-ethoxy-5-nitrobenzyl)-4-piperidinone

In 15 ml of dimethylformamide (DMF), 852 mg (2 mmol) of3-benzhydryl-1-(2-hydroxy-5-nitrobenzyl)-4-piperidinone and 552 mg (4mmol) of anhydrous potassium carbonate were stirred at room temperaturefor 15 minutes, 377 mg (2.4 mmol) of iodoethane was added thereto, andthe mixture was stirred at room temperature further for 6 hours. Ethylacetate and water were added to the reaction mixture, the mixture wasshaken and the organic layer was separated, and washed with water. Theorganic layer was dried over MgSO₄ (anhydrous), concentrated underreduced pressure and dried to obtain 875 mg of the title compound as apale yellow solid (quantitative).

¹H-NMR (CDCl₃) δ: 1.40(t, 3H), 2.43-4.50 (m, 2H), 2.54-2.61 (m, 1H),2.64-2.68 (m, 1H), 2.81-2.92 (m, 2H), 3.45-3.50 (m, 1H), 3.55 (d, 1H),3.59 (d, 1H), 4.07(q, 2H), 4.56 (d, 1H), 6.83 (d, 1H), 7.05-7.32 (m,10H), 7.88 (d, 1H), 8.13(dd, 1H), 8.33 (d, 1H).

Elemental analysis: C₂₇H₂₈N₂O₄

Calculated: C, 72.95; H, 6.35; N, 6.30.

Found: C, 72.91; H, 6.36; N, 6.03.

Example 186N-[3-[(3-Benzhydryl-4-oxo-1-piperidinyl)methyl]-4-methoxyphenyl]-N-(2,2,2-trifluoroethyl)methanesulfonamide

To a solution of 440 mg (0.92 mmol) ofN-[3-[(3-benzhydryl-4-oxo-1-piperidinyl)methyl]-4-methoxyphenyl]methanesulfonamidein 3 ml of dimethylformamide (DMF) were added 280 mg (2.03 mmol) ofanhydrous potassium carbonate and 305 mg (1.2 mmol) of2,2,2-trifluoroethyl p-toluenesulfonate, and the mixture was stirred ina water bath at 125° C. for 4 hours. Ethyl acetate and water were addedto the reaction solution, the mixture was shaken and the organic layerwas separated, and washed with water. The organic layer was dried overMgSO₄ (anhydrous) and concentrated under reduced pressure, and then theresidue was subjected to silica gel column chromatography (50 g,n-hexane-ethyl acetate 1:1, V/V) to obtain 180 mg of the title compoundas a pale yellow solid (yield: 32%).

¹H-NMR (CDCl₃) δ: 2.38-2.53 (m, 3H), 2.63-2.79 (m, 3H), 3.00 (s, 3H),3.41-3.46 (m, 1H), 3.52 (d, 1H), 3.58 (d, 1H), 3.80 (s, 3H), 4.20 (d,1H), 4.25 (d, 1H), 4.58 (d, 1H), 6.87 (d, 1H), 7.11-7.31 (m, 11H), 7.38(d, 1H).

Elemental analysis: C₂₉H₃₁F₃N₂O₄S

Calculated: C, 62.63; H, 5.62; N, 4.95.

Found: C, 62.53; H, 5.71; N, 5.01.

Example 187[3-[(3-Benzhydryl-4-oxo-1-piperidinyl)methyl]-4-methoxyphenyl]aceticAcid

(Step 1)

According to a conventional method, 3-formyl-4-methoxyphenylacetic acidmethyl ester was obtained from 2.0 g (10.3 mmol) of3-formyl-4-hydroxyphenylacetic acid methyl ester, 1.57 g (11.3 mmol) ofpotassium carbonate, methyl iodide and 5 ml of DMF.

¹H-NMR (CDCl₃) δ: 3.64 (s, 2H), 3.69 (s, 3H), 3.93 (s, 3H), 6.97 (d, 1H,J=8.8 Hz), 7.49(dd, 1H, J=8.4 Hz, J=2.4 Hz), 7.72 (d, 1H, J=2.0 Hz).

Without purification, the resultant compound was reduced with 778 mg(20.6 mmol) of sodium borohydride to obtain methyl3-hydroxymethyl-4-methoxyphenylacetate.

¹H-NMR (CDCl₃) δ: 3.57 (s, 2H), 3.68 (s, 3H), 3.85 (s, 3H), 4.67 (d, 2H,J=6.0 Hz), 6.84 (d, 1H, J=8.4 Hz), 7.17-7.20 (m, 2H).

(Step 2)

To 574.4 mg (1.90 mmol) of 3-benzhydryl-4-piperidinone hydrochloride wasadded 5 ml of dichloromethane and 1.40 g (10.8 mmol) ofdiisopropylethylamine was added thereto with stirring at roomtemperature. Then 400 mg (1.90 mmol) of methyl3-hydroxymethyl-4-methoxyphenylacetate and 571.2 mg (2.85 mmol) of EPPAwere added and the mixture was stirred for 48 hours. To the reactionmixture were added 20 ml of dichloromethane and 20 ml of a saturatedaqueous sodium hydrogen carbonate, the mixture was shaken and theorganic layer was separated, and dried over anhydrous magnesium sulfate.After concentrating under reduced pressure, the residue was purified bysilica gel column chromatography (50 g, n-hexane-ethyl acetate 4:1, V/V)to obtain methyl[3-[(3-benzhydryl-4-oxo-1-piperidinyl)methyl]-4-methoxyphenyl]acetate.

¹H-NMR (CDCl₃) δ: 2.36-2.52 (m, 3H), 2.63-2.87 (m, 3H), 3.37-3.43 (m,1H), 3.51-3.58 (m, 4H), 3.69 (s, 3H), 3.74 (s, 3H), 4.59 (d, 1H, J=11.2Hz), 6.80 (d, 1H, J=8.4 Hz), 7.09-7.32 (m, 12H).

The resultant compound was treated with hydrochloric acid to obtain 310mg of the hydrochloride (yield: 36%).

Elemental analysis: C₂₉H₃₁NO₄.HCl.1.6H₂O

Calculated: C, 66.62; H, 6.79; N, 2.68.

Found: C, 66.34; H, 6.90; N, 2.48.

IR (KBr): 2952, 1737, 1717, 1503, 1452, 1254, 1154, 1032, 748, 705, 548cm⁻¹.

(Step 3)

A solution of 150 mg (0.33 mmol) of[3-[(3-benzhydryl-4-oxo-1-piperidinyl)methyl]-4-methoxyphenyl]aceticacid methyl ester in 1.5 ml of methanol was added 0.33 ml (0.66 mmol) of2 N NaOH with stirring. After stirring at room temperature for 2 hours,the reaction mixture was concentrated under reduced pressure, 20 ml ofethyl acetate and 20 ml of water were added to the residue, the mixturewas adjusted to pH 2-3 with 1 N HCl and then shaken, and then theorganic layer was separated and washed with water. The organic layer wasdried over MgSO₄ (anhydrous) and concentrated under reduced pressure toobtain 73.1 mg of the title compound (yield: 50%).

¹H-NMR (CDCl₃) δ: 2.40-2.49 (m, 2H), 2.68-3.10 (m, 4H), 3.60 (s, 2H),3.67 (s, 3H), 3.72 (m, 3H), 4.48 (d, 1H, J=10.4 Hz), 5.35(br, 1H), 6.76(d, 1H, J=8.4 Hz), 7.08-7.32 (m, 13H).

Elemental analysis: C₂₈H₂₉NO₄.H₂O.0.5AcOEt

Calculated: C, 71.27; H, 6.98; N, 2.77.

Found: C, 71.01; H, 6.85; N, 2.61.

IR (KBr): 2934, 1718, 1598, 1506, 1453, 1258, 1136, 1032, 912, 735, 706,548 cm⁻¹.

Example 188

3-Benzhydryl-1-[2-methoxy-5-(1H-pyrrol-1-yl)benzyl]-4-piperidinone

To 473 mg (1 mmol) of1-(5-amino-2-methoxybenzyl)-3-benzhydryl-4-piperidinone-2.HCl salt wasadded 5 ml of acetic acid, and 164 mg (2 mmol) of sodium acetate wasadded thereto with stirring at room temperature. After 15 minutes, 158mg (1.2 mmol) of 2,5-dimethoxytetrahydrofuran was added and the mixturewas stirred at room temperature for 55 hours. To the reaction mixturewere added 5.5 g of anhydrous sodium carbonate, 80 ml of water and 100ml of ethyl acetate with vigorously stirring. The organic layer wasseparated, and washed with water. The organic layer was dried over MgSO₄(anhydrous) and concentrated under reduced pressure, and then theresidue was subjected to silica gel column chromatography (50 g,n-hexane-ethyl acetate 2:1, V/V) to obtain 176 mg of the title compoundas a colorless solid (yield: 39%).

¹H-NMR (CDCl₃) δ: 2.39-2.55 (m, 3H), 2.65-2.69 (m, 1H), 2.78-2.89 (m,2H), 3.37-3.51 (m, 1H), 3.58 (s, 2H), 3.79 (s, 3H), 4.57 (d, 1H),6.36(t, 2H), 6.87 (d, 1H), 7.02(t, 2H), 7.08-7.16 (m, 6H), 7.21-7.30 (m,5H), 7.38 (d, 1H).

Elemental analysis: C₃₀H₃₀N₂O₂.0.3H₂O

Calculated: C, 79.02; H, 6.76; N, 6.14.

Found: C, 78.93; H, 6.83; N, 5.95.

Example 189N-[3-[(3-Benzhydryl-4-oxo-1-piperidinyl)methyl]-4-methoxyphenyl]-2,2,2-trifluoroacetamide

To 473 mg (1 mmol) of1-(5-amino-2-methoxybenzyl)-3-benzhydryl-4-piperidinone-2.HCl salt wasadded 5 ml of pyridine, and 300 mg (1.43 mmol) of trifluoroaceticanhydride was added thereto with stirring at room temperature. Afterstirring for 0.5 hour at room temperature, 50 ml of water, 35 ml ofethyl acetate and 35 ml of hexane were added to the reaction mixture.The mixture was shaken and the organic layer was separated, and washedwith water. The organic layer was dried over MgSO₄ (anhydrous) andconcentrated under reduced pressure to obtain 467 mg of the titlecompound as a pale yellow solid (yield: 97%).

¹H-NMR (CDCl₃) δ: 2.40-2.57 (m, 3H), 2.63-2.67 (m, 1H), 2.76-2.87 (m,2H), 3.41-3.46 (m, 1H), 3.54 (s, 2H), 3.77 (s, 3H), 4.59 (d, 1H),6.83(t, 2H), 7.09 (m, 10H), 7.44(dd, 1H), 7.50 (d, 1H), 7.79(br, 1H).

Elemental analysis: C₂₈H₂₇F₃N₂O₃.0.2H₂O

Calculated: C, 67.24; H, 5.52; N, 5.60.

Found: C, 66.94; H, 5.52; N, 5.40.

Example 1903-Benzhydryl-1-[5-nitro-2-(2,2,2-trifluoroethoxy)benzyl]-4-piperidinone

To 4 ml of dimethylformamide (DMF) were added 624 mg (1.5 mmol) of3-benzhydryl-1-(2-hydroxy-5-nitrobenzyl)-4-piperidinone, 345 mg (4 mmol)of anhydrous potassium carbonate and 457 mg (1.8 mmol) of2,2,2-trifluoroethyl p-toluenesulfonate, and the mixture was stirred ina water bath at 120° C. for 9 hours and then at 115° C. for 15 hours.Ethyl acetate and water were added the reaction mixture, the mixture wasshaken and the organic layer was separated, and washed with water. Theorganic layer was dried over MgSO₄ (anhydrous) and concentrated underreduced pressure, and then the residue was subjected to silica gelcolumn chromatography (50 g, n-hexane-ethyl acetate 2:1, V/V) to obtain275 mg of the title compound as a pale yellow solid (yield: 37%).

¹H-NMR (CDCl₃) δ: 2.38-2.53 (m, 2H), 2.56-2.64 (m, 2H), 2.82-2.95 (m,2H), 3.42-3.49 (m, 1H), 3.53 (d, 1H), 3.64 (d, 1H), 4.38 (d, 1H), 4.53(d, 1H), 6.84 (d, 1H), 7.03-7.30 (m, 10H), 7.88 (d, 1H), 8.16(dd, 1H),8.34 (d, 1H).

Elemental analysis: C₂₇H₂₅F₃N₂O₄.0.3 AcOEt

Calculated: C, 64.52; H, 5.26; N, 5.34.

Found: C, 64.34; H, 4.97; N, 5.04.

Example 191N-[3-[(3-Benzhydryl-4-oxo-1-piperidinyl)methyl]-4-methoxyphenyl]ethanesulfonamide

A mixture of 473 mg (1.0 mmol) of1-(5-amino-2-methoxybenzyl)-3-benzhydryl-4-piperidinone.2HCl salt and 5ml of pyridine was stirred at room temperature, 168 mg (1.3 mmol) ofethanesulfonyl chloride was added thereto and the mixture was stirredfor 1 hour. To the reaction mixture was added 0.5 ml of water, themixture was concentrated under reduced pressure and then ethyl acetateand water were added to the residue. The mixture was shaken and then theorganic layer was separated, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to obtain 418 mg of the titlecompound as a pale yellow solid (yield: 85%).

¹H-NMR (CDCl₃) δ: 1.39(t, 3H, J=7.2 Hz), 2.36-2.42 (m, 1H), 2.53-2.64(m, 3H), 2.69-2.75 (m, 1H), 2.85-2.81 (m, 1H), 3.05(q, 2H, J=7.2 Hz),3.40-3.44 (m, 1H), 3.53 (d, 1H, J=14 Hz), 3.56 (d, 1H, J=14.4 Hz), 3.76(s, 3H), 4.65 (d, 1H, J=11.2 Hz), 6.33(br, 1H), 6.69 (d, 1H, J=11.2 Hz),7.11-7.15 (m, 3H), 7.20-7.32 (m, 9H).

Elemental analysis: C₂₈H₃₂N₂O₄S.0.1H₂O

Calculated: C, 68.02; H, 6.56; N, 5.67.

Found: C, 67.84; H, 6.66; N, 5.61.

Example 192N-[3-[(3-Benzhydryl-4-oxo-1-piperidinyl)methyl]-4-methoxyphenyl]-1-propanesulfonamide

A mixture of 284 mg (0.6 mmol) of1-(5-amino-2-methoxybenzyl)-3-benzhydryl-4-piperidinone.2HCl salt and 4ml of pyridine was stirred at room temperature, 115 mg (0.8 mmol) ofn-propanesulfonyl chloride was added thereto, and the mixture wasstirred for 1 hour. To the reaction mixture was added 0.5 ml of water,the mixture was concentrated under reduced pressure, and ethyl acetateand water were added to the residue. The mixture was shaken and theorganic layer was separated, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to obtain 286 mg of the titlecompound as a pale yellow solid (yield: 94%).

¹H-NMR (CDCl₃) δ: 1.13(t, 3H), 1.83-1.92 (m, 2H), 2.34-2.41 (m, 1H),2.53-2.64 (m, 3H), 2.69-2.75 (m, 1H), 2.85-2.91 (m, 1H), 2.98-3.02 (m,2H), 3.38-3.43 (m, 1H), 3.52 (d, 1H), 3.56 (d, 1H), 3.78 (s, 3H), 4.65(d, 1H), 6.26(br, 1H), 6.80 (d, 1H), 7.10-7.14 (m, 1H), 7.20-7.32 (m,9H)

Elemental analysis: C₂₉H₃₄N₂O₄S.0.1H₂O

Calculated: C, 68.50; H, 6.78; N, 5.51.

Found: C, 67.27; H, 6.74; N, 5.41.

Example 193 3-Benzhydryl-1-(5-bromo-2-isopropyloxybenzyl)-4-piperidinone

(Step 1)

According to a conventional method, 5-bromo-2-isopropoxybenzaldehyde wasobtained from 2.0 g (9.95 mmol) of 5-bromosalicylaldehyde, 1.51 g (10.9mmol) of potassium carbonate, 1.86 g (10.9 mmol) of 2-iodopropane and 5ml of DMF.

¹H-NMR (CDCl₃) δ: 1.40-1.41 (m, 6H), 4.64-4.67 (m, 1H), 6.89 (d, 1H,J=8.8 Hz), 7.61(dd, 1H, J=2.8 Hz, J=9.2 Hz), 7.92 (d, 1H, J=2.8 Hz),10.40 (s, 1H).

Without purification, the resultant compound was reduced with 308.9 mg(8.16 mmol) of sodium borohydride to obtain 5-bromo-2-isopropoxybenzylalcohol.

(Step 2)

To 985 mg (3.26 mmol) of 3-benzhydryl-4-piperidinone hydrochloride wasadded 8 ml of dichloromethane, and further 2.40 g (18.6 mmol) ofdiisopropylethylamine was added thereto with stirring at roomtemperature. Then, 800 mg (3.26 mmol) of 5-bromo-2-isopropoxybenzylalcohol and 979.7 mg (4.90 mmol) of EPPA were added and the mixture wasstirred for 72 hours. To the reaction mixture were added 20 ml ofdichloromethane and 20 ml of a saturated aqueous sodium hydrogencarbonate, the mixture was shaken, and the organic layer was separatedand dried over anhydrous magnesium sulfate. After concentrating underreduced pressure, the residue was purified by silica gel columnchromatography (50 g, n-hexane-ethyl acetate 6:1, V/V) to obtain thetitle compound.

¹H-NMR (CDCl₃) δ: 1.22-1.26 (m, 6H), 2.38-2.64 (m, 4H), 2.77-2.88 (m,2H), 3.38-3.42 (m, 1H), 3.46 and 3.53(ABq, 2H, J=13.6 Hz), 4.41-4.47 (m,1H), 4.57 (d, 1H, J=11.2 Hz), 6.69 (d, 1H, J=8.8 Hz), 7.08-7.32 (m,12H), 7.50 (d, 1H, J=2.4 Hz).

The resultant compound was treated with hydrochloric acid to obtain 840mg of the hydrochloride of the title compound (yield: 48%).

Elemental analysis: C₂₈H₃₀BrNO₂.HCl.0.5H₂O

Calculated: C, 62.52; H, 6.00; N, 2.60.

Found: C, 62.67; H, 6.12; N, 2.57.

IR (KBr): 3028, 2976, 2799, 1717, 1591, 1484, 1452, 1385, 1247, 1185,1115, 955, 808, 747 cm⁻¹.

Example 194 1-Benzyl-3-[(2-bromophenyl)(phenyl)methyl]-4-piperidinone

According to the same manner as that described in Example 157, the titlecompound was obtained.

¹H-NMR (CDCl₃) δ: 2.17-2.96 (m, 6H), 3.27-3.35 (m, 1H), 3.43-3.60 (m,2H), 5.28 (d, 0.5H, J=11.8 Hz), 5.32 (d, 0.5H, J=11.8 Hz), 6.94-7.53 (m,14H).

The title compound was treated with conc. hydrochloric acid and ethanolto obtain the hydrochloride of the title compound.

mp 204-206° C.

Example 195 1-Benzyl-4-[bis(4-fluorophenyl)methyl]-3-piperidinone

A mixture of 9.69 g (42.9 mmol) of 1-benzyl-3-piperidinonehydrochloride.H₂O, 150 ml of dichloromethane and 50 ml of a saturatedbrine was stirred under ice-cooling, 6.08 g (44.1 mmol) of potassiumcarbonate was added thereto and the mixture was stirred vigorously. Theprecipitated crystals were filtered off, the filtrate was allowed tostand and the dichloromethane layer was separated. The aqueous layer wasextracted once again with 150 ml of dichloromethane. The dichloromethanelayers were combined, washed with saturated brine, dried over anhydroussodium sulfate, and the solvent was distilled off under reducedpressure. The resultant 1-benzyl-3-piperidinone as a dark tan oil wasdissolved in 50 ml of dichloromethane, the solution was stirred underice-cooling, and 18 ml (99.4 mmol) of trimethylsilyl triflate (TMSOTf)and then 9.8 g (44.5 mmol) of 4,4′-difluorobenzhydrol were addedthereto. The mixture was stirred at room temperature for 26 hours, 100ml of water and 20.3 g of sodium acetate were added under ice-coolingand the mixture was adjusted to pH 9 with saturated sodium hydrogencarbonate and the dichloromethane layer was separated. Thedichloromethane layer was dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (150 g, n-hexane-ethylacetate 10:1-3:1, V/V) to obtain 8.68 g of the title compound as an oil(yield: 51.7%).

¹H-NMR (CDCl₃) δ: 1.52-1.62 (m, 1H), 1.75-1.81 (m, 1H), 2.48-3.54 (m,1H), 2.84-2.88 (m, 1H), 2.91 (d, 1H, J=13.2 Hz), 3.16 (d, 1H, J=13.8Hz), 3.18-3.24 (m, 1H), 3.58(dd, 2H, J=13.6 Hz, J=2.2 Hz), 4.39 (d, 1H,J=9.6 Hz), 6.94(t, 4H, J=8.8 Hz), 7.09-7.12 (m, 2H), 7.16-7.20 (m, 2H),7.23-7.33 (m, 5H).

The title compound was dissolved in 10 m of ethanol, and 2.4 ml (4.88mmol) of 2 N HCl was added. Then, the mixture was concentrated underreduced pressure, 4 ml of ethanol was added to the residue, and theprecipitated crystals were collected by filtration to obtain thecolorless hydrochloride of the title compound.

mp 177.5-179.0° C.

Elemental analysis: C₂₅H₂₃F₂NO.HCl.0.25H₂O (432.417)

Calculated: C, 69.44; H, 5.71; N, 3.24.

Found: C, 69.51; H, 5.71; N, 3.16.

IR (KBr): 3442, 2922, 2469, 1732, 1603, 1509, 1439, 1226, 1160, 832,750, 700, 577, 543 cm⁻¹.

Example 196 4-[Bis(4-fluorophenyl)methyl]-3-piperidinone

To a solution of 802 mg (1.87 mmol) of1-benzyl-4-[bis(4-fluorophenyl)methyl]-3-piperidinone in 50 ml ofmethanol was added 805 mg of 5% Pd—C (50% hydrated), and the mixture wasstirred at room temperature for 2 hours in a hydrogen stream. Afterfiltration, the filtrate was distilled off under reduced pressure toobtain 398 mg of the title compound (yield: 62.3%). Then it wasdissolved in ethanol, treated with conc. hydrochloric acid to obtain thehydrochloride of the title compound.

Elemental analysis: C₁₈H₁₇F₂NO.HCl.0.25H₂O

Calculated: C, 63.16; H, 5.45; N, 4.09.

Found: C, 63.38; H, 5.30; N, 4.32.

Example 1971-Benzyl-4-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-3-piperidinone

According to the same manner as that descried in Example 195, thehydrochloride of the title compound was obtained.

Elemental analysis: C₂₇H₂₇NO.HCl.0.1H₂O

Calculated: C, 77.25; H, 6.77; N, 3.34.

Found: C, 77.15; H, 6.89; N, 3.22.

Example 1984-(10,11-Dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-3-piperidinone

According to the same manner as that described in Example 196, thehydrochloride of the title compound was obtained.

mp 196-198° C. (decomp).

Elemental analysis: C₂₀H₂₁NO.HCl.0.3H₂O

Calculated: C, 72.08; H, 6.84; N, 4.20.

Found: C, 71.87; H, 6.88; N, 4.07.

Example 199 1-Acetyl-3-benzhydryl-4-piperidinone

The title compound described in Example 5 can also be produced by themethod described below.

(Step 1)

To a solution of 1.4 g (0.01 mole) of 1-acetyl-4-piperidinone and 2.2 gof 2,6-lutidine in 10 ml of dichloromethane was added 5.3 ml oftriisopropylsilyl triflate under ice-cooling. After stirring at roomtemperature for 2 hours, the mixture was washed with water and then withdiluted hydrochloric acid. After drying over magnesium sulfate, thesolvent was distilled off to obtain1-acetyl-4-piperidinonetriisopropylsilyl enolate quantitatively.

(Step 2)

To a solution of 300 mg of 1-acetyl-4-piperidinonetriisopropylsilylenolate in 5 ml of dichloromethane were added 250 mg of benzhydrylbromide and 220 mg of zinc bromide under ice-cooling. After allowing tostand overnight, an aqueous solution of sodium bicarbonate was added tothe mixture and the mixture was stirred vigorously. The dichloromethanelayer was dried over magnesium sulfate, the solvent was distilled offand the residue was purified by silica gel column chromatography (40 g,ethyl acetate). The residue was triturated with a small amount of etherand collected by filtration to obtain 140 mg of the title compound(yield: 45%).

mp 133-135° C.

Example 200 3-Benzhydryl-1-benzyl-4-piperidinone

The title compound described in Example 4 can also be produced by themethod described below. A 1 L flask was charged with 250 ml of tolueneand 73.7 g (389 mmol) of 1-benzyl-4-piperidinone and to the mixture wasadded dropwise 85.5 ml (467 mmol) of trimethylsilyl triflate withstirring under ice-cooling (internal temperature 5 to 10° C.). Thecooling bath was removed and the mixture was warmed to room temperatureand then stirred for 30 minutes. Then, 87.0 g (429 mmol) of benzhydrylchloride was added thereto and the mixture was stirred at an internaltemperature of 78 to 80° C. for 4 hours. To the mixture were added 580ml of ethyl acetate and a 10% aqueous solution of sodium carbonate withstirring under ice-cooling. After separating into layers, the aqueouslayer was washed with 580 ml of ethyl acetate. The organic layers werecombined and washed with 580 ml of water. The mixture was decolorized bytreating with 7.4 g of an active charcoal SHIRASAGI A. Afterconcentration under reduced pressure, 390 ml of ethanol and 47 ml ofconc. hydrochloric acid were added to the residue, and the mixture wasice-cooled, and allowed to stand in a refrigerator overnight. Theprecipitated crystals were collected by filtration, washed with 200 mlof ethanol and 100 ml of IPE and dried under reduced pressure to obtain107 g of the hydrochloride of the title compound (yield: 70%).

The compounds obtained in the above Examples are summarized in thefollowing Tables 1 to 3.

Table 1

Example No. R¹ R² R³ 1 H H Me 5, 199 H H Ac 6 4-Cl 4-Cl Ac 7 4-F 4-F Ac8 2-CH₂CH₂-2′ Ac 9 2-O-2′ Ac 10 H H Et 11 H H n-Pr 12 H H PhCH₂CH₂ 154-MeO 4-MeO Me 16 4-Cl 4-Cl Me 17 2-O-2′ Me 19 2-S-2′ Me 20 4-F 4-F Me23 H 4-Cl Me 25 2-CH₂CH₂-2′ Me 26 2-CH═CH-2′ Me 28 H H H 29 4-Cl 4-Cl H30 4-F 4-F H 61 H H

62 H H 2-MeOPhCH═CH—CH₂— 63 H H 2-MeOPhCH₂C(═NH)— 64 4-Cl 4-Cl2-MeOPhCH₂C(═NH)— 65 4-F 4-F 2-MeOPhCH₂C(═NH)— 66 H H

67 H H PhCONHCS— 68 H H H₂NCO— 69 H H H₂NCS— 70 H H 2-MeOPhNHCO— 71 H H2-MeOPhNHCS— 71 H H NCCH₂CH₂— 73 H H NaO₃S— 74 H H 3-Py-CH═C(NHAc)CO— 844-F 4-F 2-MeOPhCOCH₂— 87 4-F 4-F 3-PyCH₂— 89 4-F 4-F

90 4-F 4-F

124 4-Me 4-Me Ac 125 4-Me 4-Me H 131 2-CH═CH-2′ H 133 2-O-2′ H 47 H H

48 H H

50 H H

51 H H

52 H H PhCH═CHCH₂— 53 H H 3-PyCH₂— 54 H H 2-PyCH₂— 55 H H

56 H H

57 H H HC≡CCH₂— 58 H H

59 H H

60 H H

144 H H 3,5-(CF₃)₂PhCO— 145 4-Cl 4-Cl 3,5-(CF₃)₂PhCO— 146 4-F 4-F EtOCO—147 2-F H H 148 4-F 4-F

149 4-F 4-F

150 4-F 4-F

151 H H

152 H H

153 H H

154 H H

155 H H

156 H H

TABLE 2

Ex. No R¹ R² R³ R⁴ 4, 200 H H H H 13 2-O-2′ 2-MeO H 14 2-CH═CH-2′ 2-MeOH 18 2-O-2′ H H 21 4-F 4-F H H 22 4-Cl 4-Cl H H 24 H 4-Cl H H 272-CH═CH-2′ H H 32 H H 2-MeO H 34 H H 2-MeO Me 35 4-Cl 4-Cl 2-MeO H 364-F 4-F 2-MeO H 37 H H 4-MeO 4-MeOPh 38 H H 2-OH H 39 H H 3-OH H 40 H H4-OH H 41 H H 3-MeO,4-OH H 42 H H 3,4-OCH₂O— H 43 H H 2,3-(MeO)₂ H 44 HH 2,4-(MeO)₂ H 45 H H 3,4-(MeO)₂ H 46 H H 3,4,5-(MeO)₃ H 49 H H 4-MeO H75 4-F 4-F 2-OH H 76 4-F 4-F 2-MeO, 5-Br H 77 4-F 4-F 3-MeO H 78 4-F 4-F2,3,4-(MeO)₃ H 79 H 4-F 2-MeO H 80 4-F 4-F 3,5-(CF₃)₂ H 81 H H3,5-(CF₃)₂ H 82 4-F 4-F 2-F H 83 H H 2-F H 85 4-F 4-F 2-FCH₂O H 86 4-F4-F 2-PrO H 88 4-F 4-F 2-Et₂NCH₂CH₂O H 91 4-F 4-F 4-CF₃ H 92 H H 4-CF₃ H93 4-F 4-F 3-CF₃ H 94 H H 3-CF₃ H 95 4-F 4-F 2-CF₃ H 96 H H 2-CF₃ H 974-F 4-F 2-Me₂CHCH₂O H 98 4-F 4-F 2-EtO H 99 H H 2-EtO H 100 4-F 4-F2-OH, 5-NO₂ H 101 4-F 4-F 2-CN H 102 4-F 4-F 3-CN H 103 4-F 4-F 4-CN H104 4-F 4-F 4-Ph H 105 4-F 4-F 2,6-Cl₂ H 106 4-F 4-F 4-OH H 107 4-Cl4-Cl 4-OH H 108 4-F 4-F 3-PhO H 109 H H 3-PhO H 110 4-F 4-F 2,4-(CF₃)₂ H111 H H 4-Ph H 112 4-F 4-F 2-Ph H 113 H H 2-Ph H 114 4-F 4-F 2-NO₂ H 1154-F 4-F 3-NO₂ H 116 4-F 4-F 4-NO₂ H 117 4-Me 4-Me 2-MeO H 118 4-F 4-F2,6-(MeO)₂ H 119 4-F 4-F 2-F₂CHO H 120 4-F 4-F 2-CF₃O H 121 H H 4-MeS H122 H H 4-CO₂Me H 123 H H 4-CO₂H H 126 H H 4-(PhCOCH₂OCOCH₂) H 127 H H4-CH₂CO₂H H 128 H H 4-CONH₂ H 129 4-Me 4-Me 4-OH H 132 2-CH═CH-2′ 4-OH H134 2-O-2′ 4-OH H 135 4-F 4-F 2-MeO, 5-NO₂ H 136 4-F 4-F 2-MeO, 5-NH₂ H157 2-F H H H 158 2-Cl 4-Cl H H 159 4-F 4-F 2-MeO, 3, 5-(^(t)Bu)₂ H 1604-F 4-F 2-MeO, 5-MeO H 161 H H 2-MeO, 3, 5-(⁵Bu)₂ H 162 4-F 4-F 2-MeO,5-Br H (+)-form 163 4-F 4-F 2-MeO, 5-Br H (−)-form 164 4-F 4-F 2-MeS H165 H H 2-MeS H 166 4-F 4-F 2-MeO, 5-F H 167 4-F 4-F 2-MeSO H 168 H H2-MeO, 5-CF₃O H 169 4-F 4-F 2-MeO, 5-CF₃O H 170 H H 2-MeO, 6-EtO H 1714-F 4-F 2-MeO, 3, 5-Br₂ H 172 4-F 4-F 4-F 4-F-Ph 173 H H 2-MeO, 3, 5-Cl₂H 174 H H 2-MeO, 3, 5-Br₂ H 175 H H 2-MeO, 5-Pr H 176 H H 2-MeO, 5-NO₂ H177 H H 2-MeO, 5-NH₂ H 178 H H 2-MeO, 5-N(SO₂Me)₂ H 179 H H 2-MeO,5-NHAc H 180 H H

H 181 4-F 4-F 2-MeO, 5-Pr H 182 4-F 4-F 2-EtO, 5-Br H 183 H H 2-MeO,5-NHSO₂Me H 184 H H 2-OH, 5-NO₂ H 185 H H 2-EtO, 5-NO₂ H 186 H H 2-MeO,5-N(SO₂Me)CH₂CF₃ H 187 H H 2-MeO, 5-CH₂CO₂H H 188 H H

H 189 H H 2-MeO, 5-NHCOCF₃ H 190 H H 2-CF₃CH₂O, 5-NO₂ H 191 H H 2-MeO,5-NHSO₂Et H 192 H H 2-MeO, 5-NHSO₂Pr H 193 H H 2-PrO, 5-Br H 194 2-Br HH H

TABLE 3 EXAMPLE No. STRUCTURE 2

139

31

3

33

130

137

138

140

141

142

143

195

196

197

198

Preparation Example 1

(1) Compound of Example 1 10 mg (2) Lactose 60 mg (3) Corn starch 35 mg(4) Hydroxypropylmethyl cellulose  3 mg (5) Magnesium stearate  2 mg

A mixture of 10 mg of the compound obtained in Example 1, 60 mg oflactose and 35 mg of a corn starch is granulated using 0.03 ml of a 10%by weight aqueous solution of hydroxypropylmethyl cellulose (3 mg ashydroxypropylmethyl cellulose), dried at 40° C. and sieved. Theresultant granules are mixed with 2 mg of magnesium stearate andcompressed. The resultant plane tablets are coated with sugar-coating ofan aqueous suspension of sucrose, titanium dioxide, and talc and gumarabic. The coated tablets are polished with beeswax to obtain coatedtablets.

According to the same manner, coated tablets are obtained except forusing any of the compounds of Examples 2 to 200 instead of the compoundof Example 1.

Preparation Example 2

(1) Compound of Example 1 10 mg (2) Lactose 70 mg (3) Corn starch 50 mg(4) Soluble starch  7 mg (5) Magnesium stearate  3 mg

A mixture of 10 mg of the compound obtained in Example 1 and 3 mg ofmagnesium stearate is granulated with 0.07 ml of an aqueous solution ofa soluble starch (7 mg as soluble starch), dried, and mixed with 70 mgof lactose and 50 mg of corn starch. The mixture is compressed to obtaintablets.

According to the same manner, tablets are obtained except for using anyof the compounds of Examples 2 to 200 instead of the compound of Example1.

Reference Preparation Example 1

(1) Rofecoxib  5.0 mg (2) Salt 20.0 mg (3) Distilled water to total 2 ml

A solution of 5.0 mg of rofecoxib and 20.0 mg of salt in distilled wateris made up to 2.0 ml with addition of water. The solution is filtered,and filled in a 2 ml ampoule aseptically. The ampoule is sterilized,sealed to obtain a solution for injection.

Reference Preparation Example 2

(1) Rofecoxib   50 mg (2) Lactose   34 mg (3) Corn starch 10.6 mg (4)Corn starch (gelatinized)   5 mg (5) Magnesium stearate  0.4 mg (6)Calcium carboxymethyl cellulose   20 mg Total:  120 mg

According to a conventional manner, the above components (1) to (6) weremixed and compressed with a tabletting machine to obtain tablets.

Preparation Example 4

The preparation obtained in the Preparation Example 1 or 2 is combinedwith the preparation obtained in the Reference Preparation Example 1 or2.

Experiment 1

Radioligand receptor binding inhibiting activity (binding inhibitoryactivity using receptor from human lymphoblast cell (IM-9))

A modified method by M. A. Cascieri et al (Molecular Pharmacology, Vol.42, p. 458 (1992)) was employed. The receptor was prepared from a humanlymphoblast cell (IM-9). After inoculation of IM-9 cells (2×10⁵cells/ml), the cells were cultured for 3 days (1L), and then the culturewas centrifuged at 500×G for 5 minutes to obtain a cell pellet. Theresultant pellet was washed once with a phosphate buffer (FLOWLABORATORIES, CAT. No. 28-103-05), fractured in 30 ml of a 50 mMTris-HCl buffer (pH 7.4) containing 120 mM sodium chloride, 5 mMpotassium chloride, 2 μg/ml chymostatin, 40 μg/ml bacitracin, 5 μg/mlphosphoramidone, 0.5 mM phenylmethylsulfonyl fluoride and 1 mMethylenediamine tetraacetic acid using a polytron homogenizer(Kinematika, Germany), and centrifuged at 40,000×G for 20 minutes. Theseparated material was washed twice with 30 ml of the buffer solutiondescribed above and stored frozen as a receptor standard preparation(−80° C.)

This preparation was suspended in a reaction buffer [50 mM Tris-HClbuffer (pH 7.4), 0.02% bovine serum albumin, 1 mM phenylmethylsulfonylfluoride, 2 μg/ml of chymostatin, 40 μg/ml bacitracin, 3 mM manganesechloride] at a protein concentration of 0.5 mg/ml and a 100 μl portionwas used for the reaction. The sample, 125I-BHSP (0.46 KBq) was alsoadded and the mixture was reacted in a 0.2 ml reaction buffer at 25° C.for 30 minutes. A non-specific binding level was measured by addingsubstance P at 2×10⁻⁶ M.

After the reaction, a Cell Harvester [290PHD manufactured by CambridgeTechnology, Inc, USA] was used to conduct a rapid filtration over aglass filter [GF/B manufactured by Whatman, USA] whereby terminating thereaction, followed by washing three times with 250 μl of a 50 mMTris-HCl buffer solution (pH 7.4) containing 0.02% bovine serum albumin.Then, the radioactivity remaining on the filter was counted with a gammacounter. The filter was used after immersing in a 0.1% polyethyleneimine over a whole day and night followed by drying in air.

The antagonistic activity of the compound obtained in each Example wascalculated as a drug level required for accomplishing a 50% inhibitionunder the conditions specified above (IC₅₀ value), and the results areshown in Table 4. TABLE 4 Example No. IC₅₀ value (nM) 98 0.85 99 0.44163 0.62 168 0.34 175 0.42 183 0.26 185 0.29

The radioligand means [¹²⁵I]-labeled substance P.

As seen from Table 4, each compound of the present invention wasrevealed to have excellent substance P receptor antagonistic activity.

Industrial Applicability

The compound (I) of the present invention or its salt or prodrug hashigh tachykinin receptor antagonistic activity, especially highsubstance P receptor antagonistic activity, and low toxicity, thus beingemployed safely as a medicine. Accordingly, the compound (I) of thepresent invention or its salt or prodrug is useful as a pharmaceuticalcomposition, for example, a tachykinin receptor antagonist, an abnormalurination improving agent and the like.

1. A compound represented by the formula (I):

wherein each of rings A and B represents an optionally substitutedaromatic ring, or rings A and B may be bonded to each other throughlinking between bonds or substituents thereof to form a ring; ring Crepresents a nitrogenous saturated heterocyclic ring optionally havingone or more substituents besides the oxo (provided that2,3-dioxopyrrolidine ring is excluded); R¹ represents a hydrogen atom,an optionally substituted hydrocarbon group or an optionally substitutedheterocyclic group; and

represents a single bond or a double bond, or a salt thereof.
 2. Thecompound according to claim 1, wherein each of rings A and B representsan optionally substituted benzene ring, or the substituents on rings Aand B may be taken together to form a dibenzotricyclic ring.
 3. Thecompound according to claim 1, which is represented by the formula (Ia):

wherein each symbol is as defined in claim 1, or a salt thereof.
 4. Thecompound according to claim 1, which is represented by the formula (Ib):

wherein each symbol is as defined in claim 1 or a salt thereof.
 5. Thecompound according to claim 1, which is represented by the formula (Ic):

wherein each symbol is as defined in claim 1, or a salt thereof.
 6. Thecompound according to claim 1, wherein each of rings A and B is abenzene ring which may have one to three substituents selected from ahalogen atom, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, or the ringformed by binding between the bonds or substituents of rings A and B isa dibenzsuberane ring, dibenzosuberene ring, xanthene ring orthioxanthene ring.
 7. The compound according to claim 1, wherein R¹ isan optionally substituted benzyl.
 8. A prodrug of the compound accordingto claim 1, or a salt thereof.
 9. A process for producing the compoundaccording to claim 1, which comprises reacting a compound represented bythe formula (II):

wherein each symbol is as defined in claim 1, or a salt thereof with acompound represented by the formula (III):

wherein each of X and Y represents a hydrogen atom, a hydroxyl group ora halogen atom, and other symbols are as defined in claim 1, providedthat, when X is a hydrogen atom, then Y represents a hydroxyl group or ahalogen atom, while X is a halogen atom, then Y is a halogen atom, or areactive derivative or a salt thereof.
 10. A pharmaceutical compositioncomprising the compound according to claim 1, or a salt or a prodrugthereof.
 11. The pharmaceutical composition according to claim 10, whichis a tachykinin receptor antagonist.
 12. The pharmaceutical compositionaccording to claim 11, which is an agent for preventing or treatingpollakiuria, incontinence of urine, asthma, rheumatoid arthritis,osteoarthritis, pain, cough, itching, chronic obstructive pulmonarydisease, irritable bowel disease, vomiting, depression, anxietyneurosis, obsessive-compulsive neurosis, panic disorder,manic-depressive psychosis, schizophrenia, mania, migraine, cancer, HIVinfection, cardiovascular disorder, solar dermatitis, hypogonadism,ataxia, cognitive disorder or circadian rhythm disorder.
 13. A methodfor preventing or treating pollakiuria, incontinence of urine, asthma,rheumatoid arthritis, osteoarthritis, pain, cough, itching, chronicobstructive
 293. pulmonary disease, irritable bowel disease, vomiting,depression, anxiety neurosis, obsessive-compulsive neurosis, panicdisorder, manic-depressive psychosis, schizophrenia, mania, migraine,cancer, HIV infection, cardiovascular disorder, solar dermatitis,hypogonadism, ataxia, cognitive disorder or circadian rhythm disorder,which comprises administering an effective amount of the compoundaccording to claim 1, or a salt or a prodrug to thereof to a mammal. 14.Use of the compound according to claim 1, or a salt or a prodrug thereoffor manufacturing an agent for preventing or treating pollakiuria,incontinence of urine, asthma, rheumatoid arthritis, osteoarthritis,pain, cough, itching, chronic obstructive pulmonary disease, irritablebowel disease, vomiting, depression, anxiety neurosis,obsessive-compulsive neurosis, panic disorder, manic-depressivepsychosis, schizophrenia, mania, migraine, cancer, HIV infection,cardiovascular disorder, solar dermatitis, hypogonadism, ataxia,cognitive disorder or circadian rhythm disorder.